Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease.
Biomarker
Gaucher’s disease
Glucocerebrosidase
Mechanisms
Parkinson’s disease
Therapy
Journal
Translational neurodegeneration
ISSN: 2047-9158
Titre abrégé: Transl Neurodegener
Pays: England
ID NLM: 101591861
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
29
01
2024
accepted:
17
08
2024
medline:
13
9
2024
pubmed:
13
9
2024
entrez:
12
9
2024
Statut:
epublish
Résumé
Parkinson's disease (PD) is the second most common neurodegenerative disease. The development of PD is closely linked to genetic and environmental factors, with GBA1 variants being the most common genetic risk. Mutations in the GBA1 gene lead to reduced activity of the coded enzyme, glucocerebrosidase, which mediates the development of PD by affecting lipid metabolism (especially sphingolipids), lysosomal autophagy, endoplasmic reticulum, as well as mitochondrial and other cellular functions. Clinically, PD with GBA1 mutations (GBA1-PD) is characterized by particular features regarding the progression of symptom severity. On the therapeutic side, the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions. In this review, we explore the genotypic and phenotypic correlations, etiologic mechanisms, biomarkers, and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.
Identifiants
pubmed: 39267121
doi: 10.1186/s40035-024-00437-6
pii: 10.1186/s40035-024-00437-6
doi:
Substances chimiques
Glucosylceramidase
EC 3.2.1.45
GBA protein, human
EC 3.2.1.45
Biomarkers
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
48Subventions
Organisme : the National Key Plan for Scientific Research and Development of China
ID : 2021YFC2501204
Organisme : the National Natural Science Foundation of China
ID : 81873785
Organisme : the National Natural Science Foundation of China
ID : 82071439
Organisme : the National Natural Science Foundation of China
ID : 81974202
Organisme : the National Natural Science Foundation of China
ID : U20A20355
Organisme : Technology Major Project of Hunan Provincial Science and Technology Department
ID : 2021SK1010
Organisme : the Innovation-driven Team Project from Central South University
ID : 2020CX016
Organisme : the innovative team program from the Department of Science & Technology of Hunan Province
ID : 2019RS1010
Informations de copyright
© 2024. The Author(s).
Références
Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson’s disease. Lancet. 2024;403(10423):293–304.
pubmed: 38245249
doi: 10.1016/S0140-6736(23)01478-2
Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020;19(2):170–8.
pubmed: 31521533
doi: 10.1016/S1474-4422(19)30287-X
Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and pathogenesis of Parkinson’s syndrome. Annu Rev Pathol. 2023;18:95–121.
pubmed: 36100231
doi: 10.1146/annurev-pathmechdis-031521-034145
Rizig M, Bandres-Ciga S, Makarious MB, Ojo OO, Crea PW, Abiodun OV, et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. Lancet Neurol. 2023;22(11):1015–25.
pubmed: 37633302
doi: 10.1016/S1474-4422(23)00283-1
Kim JJ, Vitale D, Otani DV, Lian MM, Heilbron K, et al. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nat Genet. 2024;56(1):27–36.
pubmed: 38155330
doi: 10.1038/s41588-023-01584-8
Foo JN, Chew EGY, Chung SJ, Peng R, Blauwendraat C, Nalls MA, et al. Identification of risk loci for Parkinson disease in Asians and comparison of risk between Asians and Europeans: a genome-wide association study. JAMA Neurol. 2020;77(6):746–54.
pubmed: 32310270
doi: 10.1001/jamaneurol.2020.0428
Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091–102.
pubmed: 31701892
pmcid: 8422160
doi: 10.1016/S1474-4422(19)30320-5
Bandres-Ciga S, Saez-Atienzar S, Kim JJ, Makarious MB, Faghri F, Diez-Fairen M, et al. Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease. Acta Neuropathol. 2020;140(3):341–58.
pubmed: 32601912
pmcid: 8096770
doi: 10.1007/s00401-020-02181-3
Udayar V, Chen Y, Sidransky E, Jagasia R. Lysosomal dysfunction in neurodegeneration: emerging concepts and methods. Trends Neurosci. 2022;45(3):184–99.
pubmed: 35034773
pmcid: 8854344
doi: 10.1016/j.tins.2021.12.004
Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J, et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain. 2017;140(12):3191–203.
pubmed: 29140481
pmcid: 5841393
doi: 10.1093/brain/awx285
Horowitz M, Braunstein H, Zimran A, Revel-Vilk S, Goker-Alpan O. Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease. Adv Drug Deliv Rev. 2022;187:114402.
pubmed: 35764179
doi: 10.1016/j.addr.2022.114402
Droby A, Thaler A, Mirelman A. Imaging markers in genetic forms of Parkinson’s disease. Brain Sci. 2023;13(8):1212.
pubmed: 37626568
pmcid: 10452191
doi: 10.3390/brainsci13081212
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet. 2008;372(9645):1263–71.
pubmed: 19094956
doi: 10.1016/S0140-6736(08)61522-6
Avenali M, Cerri S, Ongari G, Ghezzi C, Pacchetti C, Tassorelli C, et al. Profiling the biochemical signature of GBA-related Parkinson’s disease in peripheral blood mononuclear cells. Mov Disord. 2021;36(5):1267–72.
pubmed: 33617695
pmcid: 8247888
doi: 10.1002/mds.28496
Thomas R, Moloney EB, Macbain ZK, Hallett PJ, Isacson O. Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2. Mol Brain. 2021;14(1):16.
pubmed: 33468204
pmcid: 7816505
doi: 10.1186/s13041-020-00712-3
Reczek D, Schwake M, Schroder J, Hughes H, Blanz J, Jin X, et al. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007;131(4):770–83.
pubmed: 18022370
doi: 10.1016/j.cell.2007.10.018
Liu Y, Li S, Wang S, Yang Q, Wu Z, Zhang M, et al. LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3beta degradation in head and neck squamous cell carcinoma. Int J Oral Sci. 2023;15(1):24.
pubmed: 37291150
pmcid: 10250453
doi: 10.1038/s41368-023-00229-0
Meng Y, Heybrock S, Neculai D, Saftig P. Cholesterol handling in lysosomes and beyond. Trends Cell Biol. 2020;30(6):452–66.
pubmed: 32413315
doi: 10.1016/j.tcb.2020.02.007
Ecard J, Lian YL, Divoux S, Gouveia Z, Vigne E, Perez F, et al. Lysosomal membrane proteins LAMP1 and LIMP2 are segregated in the Golgi apparatus independently of their clathrin adaptor binding motif. Mol Biol Cell. 2024;35(3):ar42.
pubmed: 38231876
pmcid: 10916873
doi: 10.1091/mbc.E23-06-0251
Tatti M, Motta M, Di Bartolomeo S, Cianfanelli V, Salvioli R. Cathepsin-mediated regulation of autophagy in saposin C deficiency. Autophagy. 2013;9(2):241–3.
pubmed: 23108186
pmcid: 3552889
doi: 10.4161/auto.22557
Suner L, Delhommeau F. Gaucher’s disease. N Engl J Med. 2022;386(20):1932.
pubmed: 35584158
doi: 10.1056/NEJMicm2116167
Chen Y, Sud N, Hettinghouse A, Liu CJ. Molecular regulations and therapeutic targets of Gaucher disease. Cytokine Growth Factor Rev. 2018;41:65–74.
pubmed: 29699937
pmcid: 8108120
doi: 10.1016/j.cytogfr.2018.04.003
Smith L, Mullin S, Schapira AHV. Insights into the structural biology of Gaucher disease. Exp Neurol. 2017;298(Pt B):180–90.
pubmed: 28923368
doi: 10.1016/j.expneurol.2017.09.010
Menozzi E, Toffoli M, Schapira AHV. Targeting the GBA1 pathway to slow Parkinson disease: insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues. Pharmacol Ther. 2023;246:108419.
pubmed: 37080432
doi: 10.1016/j.pharmthera.2023.108419
Do J, McKinney C, Sharma P, Sidransky E. Glucocerebrosidase and its relevance to Parkinson disease. Mol Neurodegener. 2019;14(1):36.
pubmed: 31464647
pmcid: 6716912
doi: 10.1186/s13024-019-0336-2
Gegg ME, Menozzi E, Schapira AHV. Glucocerebrosidase-associated Parkinson disease: pathogenic mechanisms and potential drug treatments. Neurobiol Dis. 2022;166:105663.
pubmed: 35183702
doi: 10.1016/j.nbd.2022.105663
Munoz SS, Petersen D, Marlet FR, Kucukkose E, Galvagnion C. The interplay between glucocerebrosidase, alpha-synuclein and lipids in human models of Parkinson’s disease. Biophys Chem. 2021;273:106534.
pubmed: 33832803
doi: 10.1016/j.bpc.2020.106534
Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2015;72(2):201–8.
pubmed: 25506732
pmcid: 4326672
doi: 10.1001/jamaneurol.2014.2950
Hanss Z, Boussaad I, Jarazo J, Schwamborn JC, Kruger R. Quality control strategy for CRISPR-Cas9-based gene editing complicated by a pseudogene. Front Genet. 2019;10:1297.
pubmed: 31998363
doi: 10.3389/fgene.2019.01297
Miyoshi K, Hagita H, Horiguchi T, Tanimura A, Noma T. Redefining GBA gene structure unveils the ability of Cap-independent, IRES-dependent gene regulation. Commun Biol. 2022;5(1):639.
pubmed: 35831491
pmcid: 9279297
doi: 10.1038/s42003-022-03577-5
Spataro N, Roca-Umbert A, Cervera-Carles L, Valles M, Anglada R, Pagonabarraga J, et al. Detection of genomic rearrangements from targeted resequencing data in Parkinson’s disease patients. Mov Disord. 2017;32(1):165–9.
pubmed: 28124432
doi: 10.1002/mds.26845
Tayebi N, Lichtenberg J, Hertz E, Sidransky E. Is Gauchian genotyping of GBA1 variants reliable? medRxiv. 2023:2023.10.26.23297627. https://doi.org/10.1101/2023.10.26.23297627 .
Toffoli M, Chen X, Sedlazeck FJ, Lee CY, Mullin S, Higgins A, et al. Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson’s disease-associated GBA gene. Commun Biol. 2022;5(1):670.
pubmed: 35794204
pmcid: 9259685
doi: 10.1038/s42003-022-03610-7
Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, et al. Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1. Orphanet J Rare Dis. 2022;17(1):442.
pubmed: 36544230
pmcid: 9768924
doi: 10.1186/s13023-022-02573-6
Jezela-Stanek A, Kleinotiene G, Chwialkowska K, Tylki-Szymanska A. Do not miss the (genetic) diagnosis of Gaucher syndrome: a narrative review on diagnostic clues and management in severe prenatal and perinatal-lethal sporadic cases. J Clin Med. 2021;10(21):4890.
pubmed: 34768410
pmcid: 8585001
doi: 10.3390/jcm10214890
Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008;29(5):567–83.
pubmed: 18338393
doi: 10.1002/humu.20676
Straniero L, Rimoldi V, Samarani M, Goldwurm S, Di Fonzo A, Kruger R, et al. The GBAP1 pseudogene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p. Sci Rep. 2017;7(1):12702.
pubmed: 28983119
pmcid: 5629250
doi: 10.1038/s41598-017-12973-5
Dos Santos JCC, Mano GBC, da Cunha Barreto-Vianna AR, Garcia TFM, de Vasconcelos AV, Sa CSG, et al. The molecular impact of glucosylceramidase beta 1 (Gba1) in Parkinson's disease: a new genetic state of the art. Mol Neurobiol. 2024;61(9):6754–70.
pubmed: 38347286
doi: 10.1007/s12035-024-04008-8
Woo EG, Tayebi N, Sidransky E. Next-generation sequencing analysis of GBA1: the challenge of detecting complex recombinant alleles. Front Genet. 2021;12:684067.
pubmed: 34234814
pmcid: 8255797
doi: 10.3389/fgene.2021.684067
Pachchek S, Landoulsi Z, Pavelka L, Schulte C, Buena-Atienza E, Gross C, et al. Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson’s study. NPJ Parkinsons Dis. 2023;9(1):156.
pubmed: 37996455
pmcid: 10667262
doi: 10.1038/s41531-023-00595-w
McKeran RO, Bradbury P, Taylor D, Stern G. Neurological involvement in type 1 (adult) Gaucher’s disease. J Neurol Neurosurg Psychiatry. 1985;48(2):172–5.
pubmed: 3981177
pmcid: 1028222
doi: 10.1136/jnnp.48.2.172
Rizig M, Bandres-Ciga S, Makarious MB, Ojo OO, Crea PW, Abiodun OV, et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. Lancet Neurol. 2023;22:1015–25.
pubmed: 37633302
doi: 10.1016/S1474-4422(23)00283-1
Alcalay RN, Dinur T, Quinn T, Sakanaka K, Levy O, Waters C, et al. Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. JAMA Neurol. 2014;71(6):752–7.
pubmed: 24756352
pmcid: 4082726
doi: 10.1001/jamaneurol.2014.313
Eblan MJ, Walker JM, Sidransky E. The glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med. 2005;352(7):728–31 (author reply 728–31).
pubmed: 15716572
doi: 10.1056/NEJM200502173520719
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–61.
pubmed: 19846850
pmcid: 2856322
doi: 10.1056/NEJMoa0901281
Migdalska-Richards A, Schapira AH. The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem. 2016;139(Suppl 1):77–90.
pubmed: 26860875
pmcid: 5111601
doi: 10.1111/jnc.13385
Lesage S, Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, et al. Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum Mol Genet. 2011;20(1):202–10.
pubmed: 20947659
doi: 10.1093/hmg/ddq454
Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015;84(9):880–7.
pubmed: 25653295
pmcid: 4351661
doi: 10.1212/WNL.0000000000001315
Parlar SC, Grenn FP, Kim JJ, Baluwendraat C, Gan-Or Z. Classification of GBA1 variants in Parkinson’s disease: the GBA1-PD browser. Mov Disord. 2023;38(3):489–95.
pubmed: 36598340
pmcid: 10033371
doi: 10.1002/mds.29314
Neumann J, Bras J, Deas E, O’Sullivan SS, Parkkinen L, Lachmann RH, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132(Pt 7):1783–94.
pubmed: 19286695
pmcid: 2702833
doi: 10.1093/brain/awp044
Zhang Y, Shu L, Sun Q, Zhou X, Pan H, Guo J, et al. Integrated Genetic analysis of racial differences of common GBA variants in Parkinson’s disease: a meta-analysis. Front Mol Neurosci. 2018;11:43.
pubmed: 29527153
pmcid: 5829555
doi: 10.3389/fnmol.2018.00043
Chen Y, Gu X, Ou R, Zhang L, Hou Y, Liu K, et al. Evaluating the role of SNCA, LRRK2, and GBA in Chinese patients with early-onset Parkinson’s disease. Mov Disord. 2020;35(11):2046–55.
pubmed: 32677286
doi: 10.1002/mds.28191
Li N, Wang L, Zhang J, Tan EK, Li J, Peng J, et al. Whole-exome sequencing in early-onset Parkinson’s disease among ethnic Chinese. Neurobiol Aging. 2020;90:150 e5-150 e11.
pubmed: 32171587
doi: 10.1016/j.neurobiolaging.2019.12.023
Yu Z, Wang T, Xu J, Wang W, Wang G, Chen C, et al. Mutations in the glucocerebrosidase gene are responsible for Chinese patients with Parkinson’s disease. J Hum Genet. 2015;60(2):85–90.
pubmed: 25518742
doi: 10.1038/jhg.2014.110
Zhao Y, Qin L, Pan H, Liu Z, Jiang L, He Y, et al. The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population. Brain. 2020;143(7):2220–34.
pubmed: 32613234
doi: 10.1093/brain/awaa167
Pulkes T, Choubtum L, Chitphuk S, Thakkinstian A, Pongpakdee S, Kulkantrakorn K, et al. Glucocerebrosidase mutations in Thai patients with Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(9):986–91.
pubmed: 24997549
doi: 10.1016/j.parkreldis.2014.06.007
Sun QY, Guo JF, Wang L, Yu RH, Zuo X, Yao LY, et al. Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson’s disease in Chinese population. Mov Disord. 2010;25(8):1005–11.
pubmed: 20131388
doi: 10.1002/mds.23009
Trinh J, Guella I, Farrer MJ. Disease penetrance of late-onset Parkinsonism: a meta-analysis. JAMA Neurol. 2014;71(12):1535–9.
pubmed: 25330418
doi: 10.1001/jamaneurol.2014.1909
Balestrino R, Tunesi S, Tesei S, Lopiano L, Zecchinelli AL, Goldwurm S. Penetrance of glucocerebrosidase (GBA) mutations in Parkinson’s disease: a Kin cohort study. Mov Disord. 2020;35(11):2111–4.
pubmed: 32767585
doi: 10.1002/mds.28200
Anheim M, Elbaz A, Lesage S, Durr A, Condroyer C, Viallet F, et al. Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology. 2012;78(6):417–20.
pubmed: 22282650
doi: 10.1212/WNL.0b013e318245f476
Menozzi E, Schapira AHV, Blandini F, Avenali M. Who is at risk of Parkinson disease? Refining the preclinical phase of GBA1 and LRRK2 variant carriers: a clinical, biochemical, and imaging approach. Curr Neurol Neurosci Rep. 2023;23(4):121–30.
pubmed: 36881256
pmcid: 10119235
doi: 10.1007/s11910-023-01259-1
Ji S, Wang C, Qiao H, Gu Z, Gan-Or Z, Fon EA, et al. Decreased penetrance of Parkinson’s disease in elderly carriers of glucocerebrosidase gene L444P/R mutations: a community-based 10-year longitudinal study. Mov Disord. 2020;35(4):672–8.
pubmed: 31912918
doi: 10.1002/mds.27971
Blauwendraat C, Reed X, Krohn L, Heilbron K, Bandres-Ciga S, Tan M, et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain. 2020;143(1):234–48.
pubmed: 31755958
doi: 10.1093/brain/awz350
Blauwendraat C, Tayebi N, Woo EG, Lopez G, Fierro L, Toffoli M, et al. Polygenic Parkinson’s disease genetic risk score as risk modifier of Parkinsonism in Gaucher disease. Mov Disord. 2023;38(5):899–903.
pubmed: 36869417
pmcid: 10271962
doi: 10.1002/mds.29342
Leonard H, Blauwendraat C, Krohn L, Faghri F, Iwaki H, Ferguson G, et al. Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease. J Med Genet. 2020;57(5):331–8.
pubmed: 31784483
doi: 10.1136/jmedgenet-2019-106283
Zhou Y, Wang Y, Wan J, Zhao Y, Pan H, Zeng Q, et al. Mutational spectrum and clinical features of GBA1 variants in a Chinese cohort with Parkinson’s disease. NPJ Parkinsons Dis. 2023;9(1):129.
pubmed: 37658046
pmcid: 10474275
doi: 10.1038/s41531-023-00571-4
Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB. New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes. JAMA Neurol. 2015;72(8):863–73.
pubmed: 26076039
doi: 10.1001/jamaneurol.2015.0703
Caminiti SP, Carli G, Avenali M, Blandini F, Perani D. Clinical and dopamine transporter imaging trajectories in a cohort of Parkinson’s disease patients with GBA mutations. Mov Disord. 2022;37(1):106–18.
pubmed: 34596920
doi: 10.1002/mds.28818
Chen YP, Yu SH, Zhang GH, Hou YB, Gu XJ, Ou RW, et al. The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson’s disease in ethnic Chinese. Eur J Neurol. 2022;29(11):3218–28.
pubmed: 35861376
doi: 10.1111/ene.15509
Maple-Grodem J, Dalen I, Tysnes OB, Macleod AD, Forsgren L, Counsell CE, et al. Association of GBA genotype with motor and functional decline in patients with newly diagnosed Parkinson disease. Neurology. 2021;96(7):e1036–44.
pubmed: 33443131
pmcid: 8055329
doi: 10.1212/WNL.0000000000011411
Stoker TB, Camacho M, Winder-Rhodes S, Liu G, Scherzer CR, Foltynie T, et al. Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2020;91(7):695–702.
pubmed: 32303560
doi: 10.1136/jnnp-2020-322857
Thaler A, Gurevich T, Bar Shira A, Gana Weisz M, Ash E, Shiner T, et al. A “dose” effect of mutations in the GBA gene on Parkinson’s disease phenotype. Parkinsonism Relat Disord. 2017;36:47–51.
pubmed: 28012950
doi: 10.1016/j.parkreldis.2016.12.014
Petrucci S, Ginevrino M, Trezzi I, Monfrini E, Ricciardi L, Albanese A, et al. GBA-related Parkinson’s disease: dissection of genotype-phenotype correlates in a large Italian cohort. Mov Disord. 2020;35(11):2106–11.
pubmed: 32658388
doi: 10.1002/mds.28195
Mullin S, Beavan M, Bestwick J, McNeill A, Proukakis C, Cox T, et al. Evolution and clustering of prodromal Parkinsonian features in GBA1 carriers. Mov Disord. 2019;34(9):1365–73.
pubmed: 31251436
pmcid: 6790937
doi: 10.1002/mds.27775
Roeben B, Liepelt-Scarfone I, Lerche S, Zimmermann M, Wurster I, Sunkel U, et al. Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers. NPJ Parkinsons Dis. 2024;10(1):88.
pubmed: 38649346
pmcid: 11035543
doi: 10.1038/s41531-024-00706-1
Liu SY, Zheng Z, Gu ZQ, Wang CD, Tang BS, Xu YM, et al. Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson’s disease. Parkinsonism Relat Disord. 2018;57:72–6.
pubmed: 30119933
doi: 10.1016/j.parkreldis.2018.08.007
Gan-Or Z, Mirelman A, Postuma RB, Arnulf I, Bar-Shira A, Dauvilliers Y, et al. GBA mutations are associated with rapid eye movement sleep behavior disorder. Ann Clin Transl Neurol. 2015;2(9):941–5.
pubmed: 26401515
pmcid: 4574811
doi: 10.1002/acn3.228
Omer N, Giladi N, Gurevich T, Bar-Shira A, Gana-Weisz M, Glinka T, et al. Glucocerebrosidase activity is not associated with Parkinson’s disease risk or severity. Mov Disord. 2022;37(1):190–5.
pubmed: 34550621
doi: 10.1002/mds.28792
Huang J, Cheng Y, Li C, Shang H. Genetic heterogeneity on sleep disorders in Parkinson’s disease: a systematic review and meta-analysis. Transl Neurodegener. 2022;11(1):21.
pubmed: 35395825
pmcid: 8991652
doi: 10.1186/s40035-022-00294-1
Avenali M, Toffoli M, Mullin S, McNeil A, Hughes DA, Mehta A, et al. Evolution of prodromal Parkinsonian features in a cohort of GBA mutation-positive individuals: a 6-year longitudinal study. J Neurol Neurosurg Psychiatry. 2019;90(10):1091–7.
pubmed: 31221723
doi: 10.1136/jnnp-2019-320394
Morris R, Martini DN, Ramsey K, Kelly VE, Smulders K, Hiller A, et al. Cognition as a mediator for gait and balance impairments in GBA-related Parkinson’s disease. NPJ Parkinsons Dis. 2022;8(1):78.
pubmed: 35725575
pmcid: 9209443
doi: 10.1038/s41531-022-00344-5
Ren J, Zhou G, Wang Y, Zhang R, Guo Z, Zhou H, et al. Association of GBA genotype with motor and cognitive decline in Chinese Parkinson’s disease patients. Front Aging Neurosci. 2023;15:1091919.
pubmed: 36845659
pmcid: 9950580
doi: 10.3389/fnagi.2023.1091919
Olszewska DA, McCarthy A, Soto-Beasley AI, Walton RL, Magennis B, McLaughlin RL, et al. Association between glucocerebrosidase mutations and Parkinson’s disease in Ireland. Front Neurol. 2020;11:527.
pubmed: 32714263
pmcid: 7344206
doi: 10.3389/fneur.2020.00527
Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I, Gasser T, et al. GBA-associated PD presents with nonmotor characteristics. Neurology. 2011;77(3):276–80.
pubmed: 21734182
doi: 10.1212/WNL.0b013e318225ab77
Jesus S, Huertas I, Bernal-Bernal I, Bonilla-Toribio M, Caceres-Redondo MT, Vargas-Gonzalez L, et al. GBA variants influence motor and non-motor features of Parkinson’s disease. PLoS ONE. 2016;11(12):e0167749.
pubmed: 28030538
pmcid: 5193380
doi: 10.1371/journal.pone.0167749
Ren J, Zhan X, Zhou H, Guo Z, Xing Y, Yin H, et al. Comparing the effects of GBA variants and onset age on clinical features and progression in Parkinson’s disease. CNS Neurosci Ther. 2023;30:e14387.
pubmed: 37563866
pmcid: 10848098
doi: 10.1111/cns.14387
Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, et al. GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015;30(3):407–11.
pubmed: 25448271
doi: 10.1002/mds.26071
Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, et al. Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Ann Neurol. 2016;80(5):674–85.
pubmed: 27717005
pmcid: 5244667
doi: 10.1002/ana.24781
Seto-Salvia N, Pagonabarraga J, Houlden H, Pascual-Sedano B, Dols-Icardo O, Tucci A, et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson’s disease course. Mov Disord. 2012;27(3):393–9.
pubmed: 22173904
doi: 10.1002/mds.24045
Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, et al. GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord. 2016;31(1):95–102.
pubmed: 26296077
doi: 10.1002/mds.26359
Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013;70(6):727–35.
pubmed: 23588557
doi: 10.1001/jamaneurol.2013.1925
Shiner T, Mirelman A, Gana Weisz M, Bar-Shira A, Ash E, Cialic R, et al. High frequency of GBA gene mutations in dementia with Lewy bodies among Ashkenazi Jews. JAMA Neurol. 2016;73(12):1448–53.
pubmed: 27723861
doi: 10.1001/jamaneurol.2016.1593
Ortega RA, Wang C, Raymond D, Bryant N, Scherzer CR, Thaler A, et al. Association of dual LRRK2 G2019S and GBA variations with Parkinson disease progression. JAMA Netw Open. 2021;4(4): e215845.
pubmed: 33881531
pmcid: 8060834
doi: 10.1001/jamanetworkopen.2021.5845
Omer N, Giladi N, Gurevich T, Bar-Shira A, Gana-Weisz M, Goldstein O, et al. A Possible modifying effect of the G2019S mutation in the LRRK2 gene on GBA Parkinson’s disease. Mov Disord. 2020;35(7):1249–53.
pubmed: 32353202
doi: 10.1002/mds.28066
Ysselstein D, Nguyen M, Young TJ, Severino A, Schwake M, Merchant K, et al. LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients. Nat Commun. 2019;10(1):5570.
pubmed: 31804465
pmcid: 6895201
doi: 10.1038/s41467-019-13413-w
Pang SY, Lo RCN, Ho PW, Liu HF, Chang EES, Leung CT, et al. LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease. Transl Neurodegener. 2022;11(1):5.
pubmed: 35101134
pmcid: 8805403
doi: 10.1186/s40035-022-00281-6
Szwedo AA, Dalen I, Pedersen KF, Camacho M, Backstrom D, Forsgren L, et al. GBA and APOE impact cognitive decline in Parkinson’s disease: a 10-year population-based study. Mov Disord. 2022;37(5):1016–27.
pubmed: 35106798
pmcid: 9362732
doi: 10.1002/mds.28932
Saha O, Melo de Farias AR, Pelletier A, Siedlecki-Wullich D, Landeira BS, Gadaut J, et al. The Alzheimer's disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons. Mol Psychiatry. 2024.
Ponnusamy M, Wang S, Yuksel M, Hansen MT, Blazier DM, McMillan JD, et al. Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model. Brain. 2023;146(4):1561–79.
pubmed: 36059072
doi: 10.1093/brain/awac318
Sudwarts A, Ramesha S, Gao T, Ponnusamy M, Wang S, Hansen M, et al. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia. Mol Neurodegener. 2022;17(1):33.
pubmed: 35526014
pmcid: 9077874
doi: 10.1186/s13024-022-00535-x
Gan-Or Z, Amshalom I, Bar-Shira A, Gana-Weisz M, Mirelman A, Marder K, et al. The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease. J Neurol. 2015;262(11):2443–7.
pubmed: 26233692
doi: 10.1007/s00415-015-7868-3
Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73(10):1217–24.
pubmed: 27571329
pmcid: 5056861
doi: 10.1001/jamaneurol.2016.2245
van der Lee SJ, van Steenoven I, van de Beek M, Tesi N, Jansen IE, van Schoor NM, et al. Genetics contributes to concomitant pathology and clinical presentation in dementia with Lewy bodies. J Alzheimers Dis. 2021;83(1):269–79.
pubmed: 34308904
pmcid: 8461715
doi: 10.3233/JAD-210365
Ren J, Zhang R, Pan C, Xu J, Sun H, Hua P, et al. Prevalence and genotype-phenotype correlations of GBA-related Parkinson disease in a large Chinese cohort. Eur J Neurol. 2022;29(4):1017–24.
pubmed: 34951095
doi: 10.1111/ene.15230
Simuni T, Uribe L, Cho HR, Caspell-Garcia C, Coffey CS, Siderowf A, et al. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson’s Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 2020;19(1):71–80.
pubmed: 31678032
doi: 10.1016/S1474-4422(19)30319-9
Davidson BA, Hassan S, Garcia EJ, Tayebi N, Sidransky E. Exploring genetic modifiers of Gaucher disease: the next horizon. Hum Mutat. 2018;39(12):1739–51.
pubmed: 30098107
pmcid: 6240360
doi: 10.1002/humu.23611
Kumar M, Srikanth MP, Deleidi M, Hallett PJ, Isacson O, Feldman RA. Acid ceramidase involved in pathogenic cascade leading to accumulation of alpha-synuclein in iPSC model of GBA1-associated Parkinson’s disease. Hum Mol Genet. 2023;32(11):1888–900.
pubmed: 36752535
pmcid: 10196677
doi: 10.1093/hmg/ddad025
Burbulla LF, Krainc D. The role of dopamine in the pathogenesis of GBA1-linked Parkinson’s disease. Neurobiol Dis. 2019;132:104545.
pubmed: 31351996
pmcid: 6834905
doi: 10.1016/j.nbd.2019.104545
Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener. 2015;4:19.
pubmed: 26464797
pmcid: 4603346
doi: 10.1186/s40035-015-0042-0
Polissidis A, Koronaiou E, Nikolopoulou G, Viel C, Nikatou M, Bogiongko M, et al. A double-hit in vivo model of GBA viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration. Neurobiol Dis. 2022;163:105612.
pubmed: 34995756
doi: 10.1016/j.nbd.2022.105612
Maor G, Rapaport D, Horowitz M. The effect of mutant GBA1 on accumulation and aggregation of alpha-synuclein. Hum Mol Genet. 2019;28(11):1768–81.
pubmed: 30615125
doi: 10.1093/hmg/ddz005
Garcia-Sanz P, Aerts JMFG, Moratalla R. The role of cholesterol in alpha-synuclein and Lewy body pathology in GBA1 Parkinson’s disease. Mov Disord. 2021;36(5):1070–85.
pubmed: 33219714
doi: 10.1002/mds.28396
Pajares M, Rojo AI, Manda G, Bosca L, Cuadrado A. Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells. 2020;9(7):1687.
pubmed: 32674367
pmcid: 7408280
doi: 10.3390/cells9071687
Henderson MX, Sedor S, McGeary I, Cornblath EJ, Peng C, Riddle DM, et al. Glucocerebrosidase activity modulates neuronal susceptibility to pathological alpha-synuclein insult. Neuron. 2020;105(5):822-836 e7.
pubmed: 31899072
doi: 10.1016/j.neuron.2019.12.004
Wong YC, Krainc D. alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1–13.
pubmed: 28170377
pmcid: 8480197
doi: 10.1038/nm.4269
Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science. 2017;357(6357):1255–61.
pubmed: 28882997
pmcid: 6021018
doi: 10.1126/science.aam9080
Nguyen M, Krainc D. LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease. Proc Natl Acad Sci U S A. 2018;115(21):5576–81.
pubmed: 29735704
pmcid: 6003526
doi: 10.1073/pnas.1717590115
Chatterjee D, Krainc D. Mechanisms of glucocerebrosidase dysfunction in Parkinson’s disease. J Mol Biol. 2023;435(12):168023.
pubmed: 36828270
pmcid: 10247409
doi: 10.1016/j.jmb.2023.168023
Rosety I, Zagare A, Saraiva C, Nickels S, Antony P, Almeida C, et al. Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids. NPJ Parkinsons Dis. 2023;9(1):166.
pubmed: 38110400
pmcid: 10728202
doi: 10.1038/s41531-023-00616-8
Behl T, Kaur G, Fratila O, Buhas C, Judea-Pusta CT, Negrut N, et al. Cross-talks among GBA mutations, glucocerebrosidase, and alpha-synuclein in GBA-associated Parkinson’s disease and their targeted therapeutic approaches: a comprehensive review. Transl Neurodegener. 2021;10(1):4.
pubmed: 33446243
pmcid: 7809876
doi: 10.1186/s40035-020-00226-x
Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146(1):37–52.
pubmed: 21700325
pmcid: 3132082
doi: 10.1016/j.cell.2011.06.001
Aflaki E, Westbroek W, Sidransky E. The complicated relationship between Gaucher disease and Parkinsonism: insights from a rare disease. Neuron. 2017;93(4):737–46.
pubmed: 28231462
pmcid: 5327952
doi: 10.1016/j.neuron.2017.01.018
Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sidransky E, et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson’s disease. Brain. 2014;137(Pt 3):834–48.
pubmed: 24477431
pmcid: 3927701
doi: 10.1093/brain/awt367
Yap TL, Gruschus JM, Velayati A, Sidransky E, Lee JC. Saposin C protects glucocerebrosidase against alpha-synuclein inhibition. Biochemistry. 2013;52(41):7161–3.
pubmed: 24070323
doi: 10.1021/bi401191v
Liu G, Chen M, Mi N, Yang W, Li X, Wang P, et al. Increased oligomerization and phosphorylation of alpha-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains. Neurobiol Aging. 2015;36(9):2649–59.
pubmed: 26149921
doi: 10.1016/j.neurobiolaging.2015.06.004
von Linstow CU, Gan-Or Z, Brundin P. Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants—let’s get even more personal. Transl Neurodegener. 2020;9(1):39.
doi: 10.1186/s40035-020-00218-x
Pchelina SN, Nuzhnyi EP, Emelyanov AK, Boukina TM, Usenko TS, Nikolaev MA, et al. Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases. Neurosci Lett. 2014;583:188–93.
pubmed: 25265039
doi: 10.1016/j.neulet.2014.09.041
Gundner AL, Duran-Pacheco G, Zimmermann S, Ruf I, Moors T, Baumann K, et al. Path mediation analysis reveals GBA impacts Lewy body disease status by increasing alpha-synuclein levels. Neurobiol Dis. 2019;121:205–13.
pubmed: 30236861
doi: 10.1016/j.nbd.2018.09.015
Gaubert S, Hourregue C, Mouton-Liger F, Millot P, Franco M, Amar-Bouaziz E, et al. Exploring the link between GBA1 mutations and Dementia with Lewy bodies, a mini-review. Neurosci Biobehav Rev. 2022;141:104856.
pubmed: 36084847
doi: 10.1016/j.neubiorev.2022.104856
Goker-Alpan O, Stubblefield BK, Giasson BI, Sidransky E. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol. 2010;120(5):641–9.
pubmed: 20838799
pmcid: 3352317
doi: 10.1007/s00401-010-0741-7
Leyns CEG, Prigent A, Beezhold B, Yao L, Hatcher NG, Tao P, et al. Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease. NPJ Parkinsons Dis. 2023;9(1):74.
pubmed: 37169750
pmcid: 10175254
doi: 10.1038/s41531-023-00517-w
Plotegher N, Bubacco L, Greggio E, Civiero L. Ceramides in Parkinson’s disease: from recent evidence to new hypotheses. Front Neurosci. 2019;13:330.
pubmed: 31001082
pmcid: 6454043
doi: 10.3389/fnins.2019.00330
Batta G, Soltesz L, Kovacs T, Bozo T, Meszar Z, Kellermayer M, et al. Alterations in the properties of the cell membrane due to glycosphingolipid accumulation in a model of Gaucher disease. Sci Rep. 2018;8(1):157.
pubmed: 29317695
pmcid: 5760709
doi: 10.1038/s41598-017-18405-8
Lerche S, Schulte C, Wurster I, Machetanz G, Roeben B, Zimmermann M, et al. The Mutation matters: CSF profiles of GCase, sphingolipids, alpha-synuclein in PD(GBA). Mov Disord. 2021;36(5):1216–28.
pubmed: 33547828
doi: 10.1002/mds.28472
Merrill AH Jr. Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev. 2011;111(10):6387–422.
pubmed: 21942574
pmcid: 3191729
doi: 10.1021/cr2002917
Taguchi YV, Liu J, Ruan J, Pacheco J, Zhang X, Abbasi J, et al. Glucosylsphingosine promotes alpha-synuclein pathology in mutant GBA-associated Parkinson’s disease. J Neurosci. 2017;37(40):9617–31.
pubmed: 28847804
pmcid: 5628407
doi: 10.1523/JNEUROSCI.1525-17.2017
Ferraz MJ, Marques AR, Appelman MD, Verhoek M, Strijland A, Mirzaian M, et al. Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases. FEBS Lett. 2016;590(6):716–25.
pubmed: 26898341
doi: 10.1002/1873-3468.12104
Lansbury P. The sphingolipids clearly play a role in Parkinson’s disease, but nature has made it complicated. Mov Disord. 2022;37(10):1985–9.
pubmed: 36087026
doi: 10.1002/mds.29204
den Heijer JM, Cullen VC, Pereira DR, Yavuz Y, de Kam ML, Grievink HW, et al. A biomarker study in patients with GBA1-Parkinson’s disease and healthy controls. Mov Disord. 2023;38(5):783–95.
doi: 10.1002/mds.29360
Galvagnion C, Brown JW, Ouberai MM, Flagmeier P, Vendruscolo M, Buell AK, et al. Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of alpha-synuclein. Proc Natl Acad Sci U S A. 2016;113(26):7065–70.
pubmed: 27298346
pmcid: 4932957
doi: 10.1073/pnas.1601899113
O’Leary EI, Jiang Z, Strub MP, Lee JC. Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated alpha-synuclein. J Biol Chem. 2018;293(28):11195–205.
pubmed: 29853639
pmcid: 6052208
doi: 10.1074/jbc.RA118.002780
Fredriksen K, Aivazidis S, Sharma K, Burbidge KJ, Pitcairn C, Zunke F, et al. Pathological alpha-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of alpha-syn in vivo. Proc Natl Acad Sci U S A. 2021;118(50):e2108489118.
pubmed: 34893541
pmcid: 8685670
doi: 10.1073/pnas.2108489118
Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, et al. Reversible conformational conversion of alpha-synuclein into toxic assemblies by glucosylceramide. Neuron. 2018;97(1):92-107 e10.
pubmed: 29290548
doi: 10.1016/j.neuron.2017.12.012
Yap TL, Jiang Z, Heinrich F, Gruschus JM, Pfefferkorn CM, Barros M, et al. Structural features of membrane-bound glucocerebrosidase and alpha-synuclein probed by neutron reflectometry and fluorescence spectroscopy. J Biol Chem. 2015;290(2):744–54.
pubmed: 25429104
doi: 10.1074/jbc.M114.610584
Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab. 2013;108(1):56–64.
pubmed: 23266198
doi: 10.1016/j.ymgme.2012.11.010
Cosden M, Jinn S, Yao L, Gretzula CA, Kandebo M, Toolan D, et al. A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy. Neurobiol Dis. 2021;159:105507.
pubmed: 34509608
doi: 10.1016/j.nbd.2021.105507
Lizama BN, Chu CT. Neuronal autophagy and mitophagy in Parkinson’s disease. Mol Aspects Med. 2021;82:100972.
pubmed: 34130867
pmcid: 8665948
doi: 10.1016/j.mam.2021.100972
Sanyal A, DeAndrade MP, Novis HS, Lin S, Chang J, Lengacher N, et al. Lysosome and inflammatory defects in GBA1-mutant astrocytes are normalized by LRRK2 inhibition. Mov Disord. 2020;35(5):760–73.
pubmed: 32034799
pmcid: 8167931
doi: 10.1002/mds.27994
Mizushima N, Levine B. Autophagy in human diseases. N Engl J Med. 2020;383(16):1564–76.
pubmed: 33053285
doi: 10.1056/NEJMra2022774
Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, et al. Autophagy in major human diseases. EMBO J. 2021;40(19):e108863.
pubmed: 34459017
pmcid: 8488577
doi: 10.15252/embj.2021108863
Nechushtai L, Frenkel D, Pinkas-Kramarski R. Autophagy in Parkinson’s disease. Biomolecules. 2023;13(10):1435.
pubmed: 37892117
pmcid: 10604695
doi: 10.3390/biom13101435
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292–5.
pubmed: 15333840
doi: 10.1126/science.1101738
Suzuki K, Iseki E, Katsuse O, Yamaguchi A, Katsuyama K, Aoki I, et al. Neuronal accumulation of alpha- and beta-synucleins in the brain of a GM2 gangliosidosis mouse model. NeuroReport. 2003;14(4):551–4.
pubmed: 12657883
doi: 10.1097/00001756-200303240-00004
Garcia-Sanz P, Orgaz L, Fuentes JM, Vicario C, Moratalla R. Cholesterol and multilamellar bodies: Lysosomal dysfunction in GBA-Parkinson disease. Autophagy. 2018;14(4):717–8.
pubmed: 29368986
pmcid: 5959320
doi: 10.1080/15548627.2018.1427396
Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol. 2010;67(12):1464–72.
pubmed: 20697033
doi: 10.1001/archneurol.2010.198
Kuo SH, Tasset I, Cheng MM, Diaz A, Pan MK, Lieberman OJ, et al. Mutant glucocerebrosidase impairs alpha-synuclein degradation by blockade of chaperone-mediated autophagy. Sci Adv. 2022;8(6):eabm6393.
pubmed: 35138901
doi: 10.1126/sciadv.abm6393
Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, et al. Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol. 2011;69(6):940–53.
pubmed: 21472771
doi: 10.1002/ana.22400
Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci. 2009;29(43):13578–88.
pubmed: 19864570
pmcid: 2812014
doi: 10.1523/JNEUROSCI.4390-09.2009
Hull A, Atilano ML, Gergi L, Kinghorn KJ. Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson’s diseases: insights for drug discovery. Philos Trans R Soc Lond B Biol Sci. 1899;2024(379):20220381.
Kinghorn KJ, Asghari AM, Castillo-Quan JI. The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson’s disease. Neural Regen Res. 2017;12(3):380–4.
pubmed: 28469644
pmcid: 5399707
doi: 10.4103/1673-5374.202934
Lunghi G, Carsana EV, Loberto N, Cioccarelli L, Prioni S, Mauri L, et al. beta-Glucocerebrosidase deficiency activates an aberrant lysosome-plasma membrane axis responsible for the onset of neurodegeneration. Cells. 2022;11(15):2343.
pubmed: 35954187
pmcid: 9367513
doi: 10.3390/cells11152343
Gegg ME, Sweet L, Wang BH, Shihabuddin LS, Sardi SP, Schapira AH. No evidence for substrate accumulation in Parkinson brains with GBA mutations. Mov Disord. 2015;30(8):1085–9.
pubmed: 26096906
pmcid: 4529481
doi: 10.1002/mds.26278
Straniero L, Rimoldi V, Monfrini E, Bonvegna S, Melistaccio G, Lake J, et al. Role of lysosomal gene variants in modulating GBA-associated Parkinson’s disease risk. Mov Disord. 2022;37(6):1202–10.
pubmed: 35262230
pmcid: 9310717
doi: 10.1002/mds.28987
Machtel R, Boros FA, Dobert JP, Arnold P, Zunke F. From lysosomal storage disorders to Parkinson’s disease—challenges and opportunities. J Mol Biol. 2023;435(12):167932.
pubmed: 36572237
doi: 10.1016/j.jmb.2022.167932
Lim SY, Tan AH, Ahmad-Annuar A, Klein C, Tan LCS, Rosales RL, et al. Parkinson’s disease in the Western Pacific region. Lancet Neurol. 2019;18(9):865–79.
pubmed: 31175000
doi: 10.1016/S1474-4422(19)30195-4
Abe T, Kuwahara T. Targeting of lysosomal pathway genes for Parkinson’s disease modification: insights from cellular and animal models. Front Neurol. 2021;12:681369.
pubmed: 34194386
pmcid: 8236816
doi: 10.3389/fneur.2021.681369
Kia DA, Zhang D, Guelfi S, Manzoni C, Hubbard L, Reynolds RH, et al. Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets. JAMA Neurol. 2021;78(4):464–72.
pubmed: 33523105
doi: 10.1001/jamaneurol.2020.5257
Zhao YW, Pan HX, Liu Z, Wang Y, Zeng Q, Fang ZH, et al. The association between lysosomal storage disorder genes and Parkinson’s disease: a large cohort study in Chinese mainland population. Front Aging Neurosci. 2021;13:749109.
pubmed: 34867278
pmcid: 8634711
doi: 10.3389/fnagi.2021.749109
Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M, Cai F, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet. 2017;49(10):1511–6.
pubmed: 28892059
pmcid: 5812477
doi: 10.1038/ng.3955
Krohn L, Ozturk TN, Vanderperre B, Ouled Amar Bencheikh B, Ruskey JA, Laurent SB, et al. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann Neurol. 2020;87(1):139–53.
pubmed: 31658403
doi: 10.1002/ana.25629
Hopfner F, Mueller SH, Szymczak S, Junge O, Tittmann L, May S, et al. Rare variants in specific lysosomal genes are associated with Parkinson’s disease. Mov Disord. 2020;35(7):1245–8.
pubmed: 32267580
doi: 10.1002/mds.28037
Tayebi N, Lopez G, Do J, Sidransky E, Pro-cathepsin D. Prosaposin, and progranulin: lysosomal networks in Parkinsonism. Trends Mol Med. 2020;26(10):913–23.
pubmed: 32948448
pmcid: 9067398
doi: 10.1016/j.molmed.2020.07.004
Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Lullmann-Rauch R, et al. LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proc Natl Acad Sci U S A. 2014;111(43):15573–8.
pubmed: 25316793
pmcid: 4217458
doi: 10.1073/pnas.1405700111
Chiasserini D, Paciotti S, Eusebi P, Persichetti E, Tasegian A, Kurzawa-Akanbi M, et al. Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener. 2015;10:15.
pubmed: 25881142
pmcid: 4428238
doi: 10.1186/s13024-015-0010-2
van Dijk KD, Persichetti E, Chiasserini D, Eusebi P, Beccari T, Calabresi P, et al. Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson’s disease. Mov Disord. 2013;28(6):747–54.
pubmed: 23712522
doi: 10.1002/mds.25495
Parnetti L, Chiasserini D, Persichetti E, Eusebi P, Varghese S, Qureshi MM, et al. Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson’s disease. Mov Disord. 2014;29(8):1019–27.
pubmed: 24436092
doi: 10.1002/mds.25772
Parnetti L, Paciotti S, Eusebi P, Dardis A, Zampieri S, Chiasserini D, et al. Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in parkinson’s disease patients. Mov Disord. 2017;32(10):1423–31.
pubmed: 28843015
doi: 10.1002/mds.27136
Oftedal L, Maple-Grodem J, Dalen I, Tysnes OB, Pedersen KF, Alves G, et al. Association of CSF glucocerebrosidase activity with the risk of incident Dementia in patients with Parkinson disease. Neurology. 2023;100(4):e388–95.
pubmed: 36253102
pmcid: 9897053
doi: 10.1212/WNL.0000000000201418
Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH. Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis. 2009;35(3):385–98.
pubmed: 19505575
doi: 10.1016/j.nbd.2009.05.023
Smith L, Schapira AHV. GBA variants and Parkinson disease: mechanisms and treatments. Cells. 2022;11(8):1261.
pubmed: 35455941
pmcid: 9029385
doi: 10.3390/cells11081261
Maor G, Cabasso O, Krivoruk O, Rodriguez J, Steller H, Segal D, et al. The contribution of mutant GBA to the development of Parkinson disease in Drosophila. Hum Mol Genet. 2016;25(13):2712–27.
pubmed: 27162249
pmcid: 6390410
Schondorf DC, Aureli M, McAllister FE, Hindley CJ, Mayer F, Schmid B, et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun. 2014;5:4028.
pubmed: 24905578
doi: 10.1038/ncomms5028
Kilpatrick BS, Magalhaes J, Beavan MS, McNeill A, Gegg ME, Cleeter MW, et al. Endoplasmic reticulum and lysosomal Ca(2)(+) stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts. Cell Calcium. 2016;59(1):12–20.
pubmed: 26691915
pmcid: 4751977
doi: 10.1016/j.ceca.2015.11.002
Fernandes HJ, Hartfield EM, Christian HC, Emmanoulidou E, Zheng Y, Booth H, et al. ER stress and autophagic perturbations lead to elevated extracellular alpha-synuclein in GBA-N370S Parkinson’s iPSC-derived dopamine neurons. Stem Cell Rep. 2016;6(3):342–56.
doi: 10.1016/j.stemcr.2016.01.013
Sanchez-Martinez A, Beavan M, Gegg ME, Chau KY, Whitworth AJ, Schapira AH. Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep. 2016;6:31380.
pubmed: 27539639
pmcid: 4990939
doi: 10.1038/srep31380
Schondorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, et al. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and Fly models of Parkinson’s disease. Cell Rep. 2018;23(10):2976–88.
pubmed: 29874584
doi: 10.1016/j.celrep.2018.05.009
Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, et al. Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains. Ann Neurol. 2012;72(3):455–63.
pubmed: 23034917
pmcid: 3638323
doi: 10.1002/ana.23614
Wright R. Mitochondrial dysfunction and Parkinson’s disease. Nat Neurosci. 2022;25(1):2.
pubmed: 34992288
doi: 10.1038/s41593-021-00989-0
Kim S, Wong YC, Gao F, Krainc D. Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease. Nat Commun. 2021;12(1):1807.
pubmed: 33753743
pmcid: 7985376
doi: 10.1038/s41467-021-22113-3
Baden P, Perez MJ, Raji H, Bertoli F, Kalb S, Illescas M, et al. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nat Commun. 2023;14(1):1930.
pubmed: 37024507
pmcid: 10079970
doi: 10.1038/s41467-023-37454-4
Rubilar JC, Outeiro TF, Klein AD. The lysosomal beta-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics. Brain. 2024;147:2610–20.
pubmed: 38437875
doi: 10.1093/brain/awae070
Klein AD, Outeiro TF. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria. Nat Commun. 2023;14(1):6383.
pubmed: 37821433
pmcid: 10567851
doi: 10.1038/s41467-023-42107-7
Cleeter MW, Chau KY, Gluck C, Mehta A, Hughes DA, Duchen M, et al. Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem Int. 2013;62(1):1–7.
pubmed: 23099359
pmcid: 3550523
doi: 10.1016/j.neuint.2012.10.010
de la Mata M, Cotan D, Oropesa-Avila M, Garrido-Maraver J, Cordero MD, Villanueva Paz M, et al. Pharmacological chaperones and coenzyme Q10 treatment improves mutant beta-glucocerebrosidase activity and mitochondrial function in neuronopathic forms of gaucher disease. Sci Rep. 2015;5:10903.
pubmed: 26045184
pmcid: 4456666
doi: 10.1038/srep10903
Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A, Brandner S, et al. Mitochondria and quality control defects in a mouse model of Gaucher disease–links to Parkinson’s disease. Cell Metab. 2013;17(6):941–53.
pubmed: 23707074
pmcid: 3678026
doi: 10.1016/j.cmet.2013.04.014
Li H, Ham A, Ma TC, Kuo SH, Kanter E, Kim D, et al. Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy. 2019;15(1):113–30.
pubmed: 30160596
doi: 10.1080/15548627.2018.1509818
Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200–10.
pubmed: 25757399
doi: 10.1016/j.tibs.2015.02.003
Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. Mitochondrial dysfunction and mitophagy in Parkinson’s disease: from mechanism to therapy. Trends Biochem Sci. 2021;46(4):329–43.
pubmed: 33323315
doi: 10.1016/j.tibs.2020.11.007
Xu YH, Xu K, Sun Y, Liou B, Quinn B, Li RH, et al. Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Hum Mol Genet. 2014;23(15):3943–57.
pubmed: 24599400
pmcid: 4082362
doi: 10.1093/hmg/ddu105
Munoz-Delgado L, Macias-Garcia D, Perinan MT, Jesus S, Adarmes-Gomez AD, Bonilla Toribio M, et al. Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease. NPJ Parkinsons Dis. 2023;9(1):12.
pubmed: 36720879
pmcid: 9889312
doi: 10.1038/s41531-023-00457-5
Pandey MK, Burrow TA, Rani R, Martin LJ, Witte D, Setchell KD, et al. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature. 2017;543(7643):108–12.
pubmed: 28225753
doi: 10.1038/nature21368
Boddupalli CS, Nair S, Belinsky G, Gans J, Teeple E, Nguyen TH, et al. Neuroinflammation in neuronopathic Gaucher disease: role of microglia and NK cells, biomarkers, and response to substrate reduction therapy. Elife. 2022;11:e79830.
pubmed: 35972072
pmcid: 9381039
doi: 10.7554/eLife.79830
Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27.
pubmed: 30275469
doi: 10.1038/s41572-018-0025-4
Rocha EM, Smith GA, Park E, Cao H, Graham AR, Brown E, et al. Sustained systemic glucocerebrosidase inhibition induces brain alpha-synuclein aggregation, microglia and complement C1q activation in mice. Antioxid Redox Signal. 2015;23(6):550–64.
pubmed: 26094487
pmcid: 4544823
doi: 10.1089/ars.2015.6307
Mus L, Siani F, Giuliano C, Ghezzi C, Cerri S, Blandini F. Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity. Neurobiol Dis. 2019;124:289–96.
pubmed: 30521842
doi: 10.1016/j.nbd.2018.12.001
Usenko T, Bezrukova A, Rudenok MM, Basharova K, Shadrina MI, Slominsky PA, et al. Whole transcriptome analysis of substantia Nigra in mice with MPTP-induced parkinsonism bearing defective glucocerebrosidase activity. Int J Mol Sci. 2023;24(15):12164.
pubmed: 37569538
pmcid: 10418497
doi: 10.3390/ijms241512164
Miliukhina IV, Usenko TS, Senkevich KA, Nikolaev MA, Timofeeva AA, Agapova EA, et al. Plasma cytokines profile in patients with Parkinson’s disease associated with mutations in GBA gene. Bull Exp Biol Med. 2020;168(4):423–6.
pubmed: 32146630
doi: 10.1007/s10517-020-04723-x
Chahine LM, Qiang J, Ashbridge E, Minger J, Yearout D, Horn S, et al. Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations. JAMA Neurol. 2013;70(7):852–8.
pubmed: 23699752
pmcid: 3762458
doi: 10.1001/jamaneurol.2013.1274
Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ, et al. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell. 2016;15(1):77–88.
pubmed: 26486234
doi: 10.1111/acel.12409
Bo RX, Li YY, Zhou TT, Chen NH, Yuan YH. The neuroinflammatory role of glucocerebrosidase in Parkinson’s disease. Neuropharmacology. 2022;207:108964.
pubmed: 35065083
doi: 10.1016/j.neuropharm.2022.108964
Pitcairn C, Wani WY, Mazzulli JR. Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson’s disease. Neurobiol Dis. 2019;122:72–82.
pubmed: 29550539
doi: 10.1016/j.nbd.2018.03.008
Kim J, Daadi EW, Oh T, Daadi ES, Daadi MM. Human induced pluripotent stem cell phenotyping and preclinical modeling of familial Parkinson’s disease. Genes (Basel). 2022;13(11):1937.
pubmed: 36360174
doi: 10.3390/genes13111937
Yarkova ES, Grigor’eva EV, Medvedev SP, Pavlova SV, Zakian SM, Malakhova AA. IPSC-derived astrocytes contribute to in vitro modeling of Parkinson’s disease caused by the GBA1 N370S mutation. Int J Mol Sci. 2023;25(1):327.
pubmed: 38203497
pmcid: 10779194
doi: 10.3390/ijms25010327
Eichmuller OL, Knoblich JA. Human cerebral organoids—a new tool for clinical neurology research. Nat Rev Neurol. 2022;18(11):661–80.
pubmed: 36253568
pmcid: 9576133
doi: 10.1038/s41582-022-00723-9
Zagare A, Barmpa K, Smajic S, Smits LM, Grzyb K, Grunewald A, et al. Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression. Am J Hum Genet. 2022;109(2):311–27.
pubmed: 35077669
pmcid: 8874228
doi: 10.1016/j.ajhg.2021.12.009
Yahya V, Di Fonzo A, Monfrini E. Genetic evidence for endolysosomal dysfunction in Parkinson’s disease: a critical overview. Int J Mol Sci. 2023;24(7):6338.
pubmed: 37047309
pmcid: 10094484
doi: 10.3390/ijms24076338
Sanchiz-Calvo M, Bentea E, Baekelandt V. Rodent models based on endolysosomal genes involved in Parkinson’s disease. Curr Opin Neurobiol. 2022;72:55–62.
pubmed: 34628360
doi: 10.1016/j.conb.2021.09.004
Migdalska-Richards A, Wegrzynowicz M, Rusconi R, Deangeli G, Di Monte DA, Spillantini MG, et al. The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice. Brain. 2017;140(10):2706–21.
pubmed: 28969384
pmcid: 5841155
doi: 10.1093/brain/awx221
Migdalska-Richards A, Wegrzynowicz M, Harrison IF, Verona G, Bellotti V, Spillantini MG, et al. L444P Gba1 mutation increases formation and spread of alpha-synuclein deposits in mice injected with mouse alpha-synuclein pre-formed fibrils. PLoS ONE. 2020;15(8):e0238075.
pubmed: 32833982
pmcid: 7444808
doi: 10.1371/journal.pone.0238075
Zhao X, Lin Y, Liou B, Fu W, Jian J, Fannie V, et al. PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proc Natl Acad Sci U S A. 2023;120(1):e2210442120.
pubmed: 36574647
doi: 10.1073/pnas.2210442120
Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, et al. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain. 2015;138(Pt 9):2648–58.
pubmed: 26117366
pmcid: 4564023
doi: 10.1093/brain/awv179
Huh YE, Chiang MSR, Locascio JJ, Liao Z, Liu G, Choudhury K, et al. beta-Glucocerebrosidase activity in GBA-linked Parkinson disease: the type of mutation matters. Neurology. 2020;95(6):e685–96.
pubmed: 32540937
pmcid: 7455354
doi: 10.1212/WNL.0000000000009989
Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163–75.
pubmed: 23510062
doi: 10.1615/CritRevOncog.2013006060
Atashrazm F, Hammond D, Perera G, Dobson-Stone C, Mueller N, Pickford R, et al. Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease. Sci Rep. 2018;8(1):15446.
pubmed: 30337601
pmcid: 6193988
doi: 10.1038/s41598-018-33921-x
Kedariti M, Frattini E, Baden P, Cogo S, Civiero L, Ziviani E, et al. LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease. NPJ Parkinsons Dis. 2022;8(1):92.
pubmed: 35853899
pmcid: 9296523
doi: 10.1038/s41531-022-00354-3
Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 2013;16(4):394–406.
pubmed: 23455607
pmcid: 3609872
doi: 10.1038/nn.3350
MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron. 2013;77(3):425–39.
pubmed: 23395371
pmcid: 3646583
doi: 10.1016/j.neuron.2012.11.033
Te Vruchte D, Sturchio A, Priestman DA, Tsitsi P, Hertz E, Andreasson M, et al. Glycosphingolipid changes in plasma in Parkinson’s disease independent of glucosylceramide levels. Mov Disord. 2022;37(10):2129–34.
doi: 10.1002/mds.29163
Huebecker M, Moloney EB, van der Spoel AC, Priestman DA, Isacson O, Hallett PJ, et al. Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease. Mol Neurodegener. 2019;14(1):40.
pubmed: 31703585
pmcid: 6842240
doi: 10.1186/s13024-019-0339-z
Surface M, Balwani M, Waters C, Haimovich A, Gan-Or Z, Marder KS, et al. Plasma glucosylsphingosine in GBA1 mutation carriers with and without Parkinson’s disease. Mov Disord. 2022;37(2):416–21.
pubmed: 34741486
doi: 10.1002/mds.28846
Rocha EM, Smith GA, Park E, Cao H, Brown E, Hallett P, et al. Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann Clin Transl Neurol. 2015;2(4):433–8.
pubmed: 25909088
pmcid: 4402088
doi: 10.1002/acn3.177
Blumenreich S, Nehushtan T, Barav OB, Saville JT, Dingjan T, Hardy J, et al. Elevation of gangliosides in four brain regions from Parkinson’s disease patients with a GBA mutation. NPJ Parkinsons Dis. 2022;8(1):99.
pubmed: 35933559
pmcid: 9357011
doi: 10.1038/s41531-022-00363-2
Huh YE, Park H, Chiang MSR, Tuncali I, Liu G, Locascio JJ, et al. Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI. NPJ Parkinsons Dis. 2021;7(1):102.
pubmed: 34811369
pmcid: 8608962
doi: 10.1038/s41531-021-00241-3
Ysselstein D, Young TJ, Nguyen M, Padmanabhan S, Hirst WD, Dzamko N, et al. Evaluation of strategies for measuring lysosomal glucocerebrosidase activity. Mov Disord. 2021;36(12):2719–30.
pubmed: 34613624
pmcid: 8853444
doi: 10.1002/mds.28815
Oftedal L, Maple-Grodem J, Forland MGG, Alves G, Lange J. Validation and assessment of preanalytical factors of a fluorometric in vitro assay for glucocerebrosidase activity in human cerebrospinal fluid. Sci Rep. 2020;10(1):22098.
pubmed: 33328543
pmcid: 7744549
doi: 10.1038/s41598-020-79104-5
Farfel-Becker T, Do J, Tayebi N, Sidransky E. Can GBA1-associated Parkinson disease be modeled in the mouse? Trends Neurosci. 2019;42(9):631–43.
pubmed: 31288942
doi: 10.1016/j.tins.2019.05.010
Sosero YL, Yu E, Krohn L, Rudakou U, Mufti K, Ruskey JA, et al. LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson’s disease. Neurobiol Aging. 2021;103:142 e1-142 e5.
pubmed: 33781610
doi: 10.1016/j.neurobiolaging.2021.02.018
Cecioni S, Ashmus RA, Gilormini PA, Zhu S, Chen X, Shan X, et al. Quantifying lysosomal glycosidase activity within cells using bis-acetal substrates. Nat Chem Biol. 2022;18(3):332–41.
pubmed: 35210619
doi: 10.1038/s41589-021-00960-x
Senkevich K, Rudakou U, Gan-Or Z. New therapeutic approaches to Parkinson’s disease targeting GBA, LRRK2 and Parkin. Neuropharmacology. 2022;202:108822.
pubmed: 34626666
doi: 10.1016/j.neuropharm.2021.108822
Sardi SP, Viel C, Clarke J, Treleaven CM, Richards AM, Park H, et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc Natl Acad Sci U S A. 2017;114(10):2699–704.
pubmed: 28223512
pmcid: 5347608
doi: 10.1073/pnas.1616152114
Viel C, Clarke J, Kayatekin C, Richards AM, Chiang MSR, Park H, et al. Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model. Sci Rep. 2021;11(1):20945.
pubmed: 34686711
pmcid: 8536659
doi: 10.1038/s41598-021-00404-5
Giladi N, Alcalay RN, Cutter G, Gasser T, Gurevich T, Hoglinger GU, et al. Safety and efficacy of venglustat in GBA1-associated Parkinson’s disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2023;22(8):661–71.
pubmed: 37479372
doi: 10.1016/S1474-4422(23)00205-3
Peterschmitt MJ, Saiki H, Hatano T, Gasser T, Isaacson SH, Gaemers SJM, et al. Safety, pharmacokinetics, and pharmacodynamics of oral venglustat in patients with Parkinson’s disease and a GBA mutation: results from part 1 of the randomized, double-blinded, placebo-controlled MOVES-PD trial. J Parkinsons Dis. 2022;12(2):557–70.
pubmed: 34897099
pmcid: 8925113
doi: 10.3233/JPD-212714
Huh YE, Usnich T, Scherzer CR, Klein C, Chung SJ. GBA1 variants and Parkinson’s disease: paving the way for targeted therapy. J Mov Disord. 2023;16(3):261–78.
pubmed: 37302978
pmcid: 10548077
doi: 10.14802/jmd.23023
Zimran A, Revel-Vilk S, Becker-Cohen M, Istaiti M, Rolfs A. Venglustat in GBA1-related Parkinson’s disease. Lancet Neurol. 2024;23(2):137.
pubmed: 38267177
doi: 10.1016/S1474-4422(23)00455-6
Istaiti M, Revel-Vilk S, Becker-Cohen M, Dinur T, Ramaswami U, Castillo-Garcia D, et al. Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: investigator initiated registry based on real life data. Am J Hematol. 2021;96(5):545–51.
pubmed: 33606887
doi: 10.1002/ajh.26131
Santana AG, Robinson K, Vickers C, Deen MC, Chen HM, Zhou S, et al. Pharmacological chaperones for GCase that switch conformation with pH enhance enzyme levels in Gaucher animal models. Angew Chem Int Ed Engl. 2022;61(38):e202207974.
pubmed: 35864061
doi: 10.1002/anie.202207974
Zhang K, Zhu S, Li J, Jiang T, Feng L, Pei J, et al. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease. Acta Pharm Sin B. 2021;11(10):3015–34.
pubmed: 34729301
pmcid: 8546670
doi: 10.1016/j.apsb.2021.02.016
Martinez-Bailen M, Clemente F, Matassini C, Cardona F. GCase enhancers: a potential therapeutic option for gaucher disease and other neurological disorders. Pharmaceuticals (Basel). 2022;15(7):823.
pubmed: 35890122
doi: 10.3390/ph15070823
Kopytova AE, Rychkov GN, Cheblokov AA, Grigor’eva EV, Nikolaev MA, Yarkova ES, et al. Potential binding sites of pharmacological chaperone NCGC00241607 on mutant beta-glucocerebrosidase and its efficacy on patient-derived cell cultures in gaucher and Parkinson’s disease. Int J Mol Sci. 2023;24(10):9105.
pubmed: 37240451
pmcid: 10219579
doi: 10.3390/ijms24109105
Han TU, Sam R, Sidransky E. Small molecule chaperones for the treatment of Gaucher disease and GBA1-associated Parkinson disease. Front Cell Dev Biol. 2020;8:271.
pubmed: 32509770
pmcid: 7248408
doi: 10.3389/fcell.2020.00271
Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D. A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease. Sci Transl Med. 2019;11(514):eaau6870.
pubmed: 31619543
pmcid: 7359409
doi: 10.1126/scitranslmed.aau6870
Mullin S, Smith L, Lee K, D’Souza G, Woodgate P, Elflein J, et al. Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial. JAMA Neurol. 2020;77(4):427–34.
pubmed: 31930374
pmcid: 6990847
doi: 10.1001/jamaneurol.2019.4611
Yang SY, Taanman JW, Gegg M, Schapira AHV. Ambroxol reverses tau and alpha-synuclein accumulation in a cholinergic N370S GBA1 mutation model. Hum Mol Genet. 2022;31(14):2396–405.
pubmed: 35179198
pmcid: 9307316
doi: 10.1093/hmg/ddac038
Siemeling O, Slingerland S, van der Zee S, van Laar T. Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation. BMC Neurol. 2024;24(1):146.
pubmed: 38693511
pmcid: 11061939
doi: 10.1186/s12883-024-03629-9
Cyske Z, Gaffke L, Rintz E, Wisniewska K, Wegrzyn G, Pierzynowska K. Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease. Neurochem Int. 2024;178:105774.
pubmed: 38797393
doi: 10.1016/j.neuint.2024.105774
McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014;137(Pt 5):1481–95.
pubmed: 24574503
pmcid: 3999713
doi: 10.1093/brain/awu020
Ambrosi G, Ghezzi C, Zangaglia R, Levandis G, Pacchetti C, Blandini F. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson’s disease cells. Neurobiol Dis. 2015;82:235–42.
pubmed: 26094596
doi: 10.1016/j.nbd.2015.06.008
Magalhaes J, Gegg ME, Migdalska-Richards A, Schapira AH. Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons. Sci Rep. 2018;8(1):1385.
pubmed: 29362387
pmcid: 5780491
doi: 10.1038/s41598-018-19479-8
Mishra A, Krishnamurthy S. Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(3):429–44.
pubmed: 31654086
doi: 10.1007/s00210-019-01737-9
Migdalska-Richards A, Daly L, Bezard E, Schapira AH. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann Neurol. 2016;80(5):766–75.
pubmed: 27859541
pmcid: 5132106
doi: 10.1002/ana.24790
Vieira SRL, Schapira AHV. Glucocerebrosidase mutations and Parkinson disease. J Neural Transm (Vienna). 2022;129(9):1105–17.
pubmed: 35932311
doi: 10.1007/s00702-022-02531-3
Toffoli M, Smith L, Schapira AHV. The biochemical basis of interactions between glucocerebrosidase and alpha-synuclein in GBA1 mutation carriers. J Neurochem. 2020;154(1):11–24.
pubmed: 31965564
doi: 10.1111/jnc.14968
Okano H, Morimoto S. iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders. Cell Stem Cell. 2022;29(2):189–208.
pubmed: 35120619
doi: 10.1016/j.stem.2022.01.007
Mansour HM, El-Khatib AS. Exploring Parkinson-associated kinases for CRISPR/Cas9-based gene editing: beyond alpha-synuclein. Ageing Res Rev. 2023;92:102114.
pubmed: 37924981
doi: 10.1016/j.arr.2023.102114
Kim MS, Ra EA, Kweon SH, Seo BA, Ko HS, Oh Y, et al. Advanced human iPSC-based preclinical model for Parkinson’s disease with optogenetic alpha-synuclein aggregation. Cell Stem Cell. 2023;30(7):973-986 e11.
pubmed: 37339636
pmcid: 10829432
doi: 10.1016/j.stem.2023.05.015
Kim MJ, Kim S, Reinheckel T, Krainc D. Inhibition of cysteine protease cathepsin Lincreases the level and activity of lysosomal glucocerebrosidase. JCI Insight. 2024;9(3).
Gehrlein A, Udayar V, Anastasi N, Morella ML, Ruf I, Brugger D, et al. Targeting neuronal lysosomal dysfunction caused by beta-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct. Nat Commun. 2023;14(1):2057.
pubmed: 37045813
pmcid: 10097658
doi: 10.1038/s41467-023-37632-4
Chen C, Hertz E, Chen Y, Sidransky E. Targeting protein clearance pathways in GBA1-associated Parkinson disease. Expert Opin Ther Targets. 2022;26(12):1031–5.
pubmed: 36628605
doi: 10.1080/14728222.2022.2166828
Ryan E, Seehra G, Sharma P, Sidransky E. GBA1-associated Parkinsonism: new insights and therapeutic opportunities. Curr Opin Neurol. 2019;32(4):589–96.
pubmed: 31188151
doi: 10.1097/WCO.0000000000000715
Peng Y, Liou B, Lin Y, Mayhew CN, Fleming SM, Sun Y. iPSC-derived neural precursor cells engineering GBA1 recovers acid beta-glucosidase deficiency and diminishes alpha-synuclein and neuropathology. Mol Ther Methods Clin Dev. 2023;29:185–201.
pubmed: 37063480
pmcid: 10102010
doi: 10.1016/j.omtm.2023.03.007
Jo J, Yang L, Tran HD, Yu W, Sun AX, Chang YY, et al. Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and alpha-synuclein mutations. Ann Neurol. 2021;90(3):490–505.
pubmed: 34288055
pmcid: 9543721
doi: 10.1002/ana.26166
Gegg ME, Verona G, Schapira AHV. Glucocerebrosidase deficiency promotes release of alpha-synuclein fibrils from cultured neurons. Hum Mol Genet. 2020;29(10):1716–28.
pubmed: 32391886
pmcid: 7322566
doi: 10.1093/hmg/ddaa085
Baden P, Yu C, Deleidi M. Insights into GBA Parkinson’s disease pathology and therapy with induced pluripotent stem cell model systems. Neurobiol Dis. 2019;127:1–12.
pubmed: 30711484
doi: 10.1016/j.nbd.2019.01.023
Yang W, Li X, Yin N. Increased alpha-synuclein oligomerization is associated with decreased activity of glucocerebrosidase in the aging human striatum and hippocampus. Neurosci Lett. 2020;733:135093.
pubmed: 32470554
doi: 10.1016/j.neulet.2020.135093
Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener. 2017;12(1):10.
pubmed: 28118852
pmcid: 5259880
doi: 10.1186/s13024-017-0149-0
Bae EJ, Yang NY, Song M, Lee CS, Lee JS, Jung BC, et al. Glucocerebrosidase depletion enhances cell-to-cell transmission of alpha-synuclein. Nat Commun. 2014;5:4755.
pubmed: 25156829
doi: 10.1038/ncomms5755
Bae EJ, Yang NY, Lee C, Lee HJ, Kim S, Sardi SP, et al. Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation. Exp Mol Med. 2015;47(3):e153.
pubmed: 25813221
pmcid: 4351412
doi: 10.1038/emm.2014.128
Fishbein I, Kuo YM, Giasson BI, Nussbaum RL. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation. Brain. 2014;137(Pt 12):3235–47.
pubmed: 25351739
pmcid: 4240298
doi: 10.1093/brain/awu291
Papadopoulos VE, Nikolopoulou G, Antoniadou I, Karachaliou A, Arianoglou G, Emmanouilidou E, et al. Modulation of beta-glucocerebrosidase increases alpha-synuclein secretion and exosome release in mouse models of Parkinson’s disease. Hum Mol Genet. 2018;27(10):1696–710.
pubmed: 29547959
Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A. 2013;110(9):3537–42.
pubmed: 23297226
pmcid: 3587272
doi: 10.1073/pnas.1220464110
Deng YN, Shi J, Liu J, Qu QM. Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int. 2013;63(1):1–9.
pubmed: 23619395
doi: 10.1016/j.neuint.2013.04.005