A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
08 Jan 2024
08 Jan 2024
Historique:
received:
19
04
2023
accepted:
14
12
2023
medline:
9
1
2024
pubmed:
9
1
2024
entrez:
9
1
2024
Statut:
epublish
Résumé
Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.
Identifiants
pubmed: 38191886
doi: 10.1038/s41531-023-00624-8
pii: 10.1038/s41531-023-00624-8
doi:
Types de publication
Journal Article
Langues
eng
Pagination
12Subventions
Organisme : Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)
ID : 019358
Organisme : Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)
ID : 020338
Organisme : Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)
ID : 019358
Informations de copyright
© 2024. The Author(s).
Références
Cheng, H. C., Ulane, C. M. & Burke, R. E. Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715–725 (2010).
pubmed: 20517933
pmcid: 2918373
doi: 10.1002/ana.21995
Marras, C. & Lang, A. Parkinson’s disease subtypes: lost in translation? J. Neurol. Neurosurg. Psychiatry 84, 409–415 (2013).
pubmed: 22952329
doi: 10.1136/jnnp-2012-303455
Mestre, T. A. et al. Parkinson’s disease subtypes: critical appraisal and recommendations. J. Parkinsons Dis. 11, 395–404 (2021).
pubmed: 33682731
pmcid: 8150501
doi: 10.3233/JPD-202472
Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 7, 583–590 (2008).
pubmed: 18539534
pmcid: 2832754
doi: 10.1016/S1474-4422(08)70117-0
Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 46, 989–993 (2014).
pubmed: 25064009
pmcid: 4146673
doi: 10.1038/ng.3043
Simon-Sanchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat. Genet. 41, 1308–1312 (2009).
pmcid: 2787725
doi: 10.1038/ng.487
Sharma, M. et al. Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology 79, 659–667 (2012).
pubmed: 22786590
pmcid: 3414661
doi: 10.1212/WNL.0b013e318264e353
Kluss, J. H., Mamais, A. & Cookson, M. R. LRRK2 links genetic and sporadic Parkinson’s disease. Biochem. Soc. Trans. 47, 651–661 (2019).
pubmed: 30837320
pmcid: 6563926
doi: 10.1042/BST20180462
Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife https://doi.org/10.7554/eLife.12813 (2016).
Sheng, Z. et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4, 164ra161 (2012).
pubmed: 23241745
doi: 10.1126/scitranslmed.3004485
Mir, R. et al. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem. J. 475, 1861–1883 (2018).
pubmed: 29743203
doi: 10.1042/BCJ20180248
Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aar5429 (2018).
Fernandez, B. et al. Evaluation of current methods to detect cellular leucine-rich repeat kinase 2 (LRRK2) kinase activity. J. Parkinsons Dis. 12, 1423–1447 (2022).
pubmed: 35599495
pmcid: 9398093
doi: 10.3233/JPD-213128
Wallings, R. L., Herrick, M. K. & Tansey, M. G. LRRK2 at the interface between peripheral and central immune function in Parkinson’s. Front. Neurosci. 14, 443 (2020).
pubmed: 32508566
pmcid: 7253584
doi: 10.3389/fnins.2020.00443
Kluss, J. H. et al. Detection of endogenous S1292 LRRK2 autophosphorylation in mouse tissue as a readout for kinase activity. NPJ Parkinsons Dis. 4, 13 (2018).
pubmed: 29707617
pmcid: 5908918
doi: 10.1038/s41531-018-0049-1
Steger, M. et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. Elife https://doi.org/10.7554/eLife.31012 (2017).
Pfeffer, S. R. Rab GTPases: master regulators of membrane trafficking. Curr. Opin. Cell Biol. 6, 522–526 (1994).
pubmed: 7986528
doi: 10.1016/0955-0674(94)90071-X
Rideout, H. J. et al. The current state-of-the art of LRRK2-based biomarker assay development in Parkinson’s disease. Front. Neurosci. 14, 865 (2020).
pubmed: 33013290
pmcid: 7461933
doi: 10.3389/fnins.2020.00865
Fan, Y. et al. Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem. J. 475, 23–44 (2018).
pubmed: 29127255
doi: 10.1042/BCJ20170803
Atashrazm, F. et al. LRRK2-mediated Rab10 phosphorylation in immune cells from Parkinson’s disease patients. Mov. Disord. 34, 406–415 (2019).
doi: 10.1002/mds.27601
Nirujogi, R. S. et al. Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites. Biochem. J. 478, 299–326 (2021).
pubmed: 33367571
doi: 10.1042/BCJ20200930
Fan, Y. et al. R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils. Acta Neuropathol. 142, 475–494 (2021).
pubmed: 34125248
pmcid: 8357670
doi: 10.1007/s00401-021-02325-z
Karayel, O. et al. Accurate MS-based Rab10 phosphorylation stoichiometry determination as readout for LRRK2 activity in Parkinson’s disease. Mol. Cell. Proteomics 19, 1546–1560 (2020).
pubmed: 32601174
pmcid: 8143643
doi: 10.1074/mcp.RA120.002055
Padmanabhan, S. et al. An assessment of LRRK2 serine 935 phosphorylation in human peripheral blood mononuclear cells in idiopathic Parkinson’s disease and G2019S LRRK2 cohorts. J. Parkinsons Dis. 10, 623–629 (2020).
pubmed: 32007961
pmcid: 7242833
doi: 10.3233/JPD-191786
Wang, X. et al. Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10. Sci. Rep. 11, 12900 (2021).
pubmed: 34145320
pmcid: 8213766
doi: 10.1038/s41598-021-91943-4
Wallings, R. L. et al. WHOPPA enables parallel assessment of leucine-rich repeat kinase 2 and glucocerebrosidase enzymatic activity in Parkinson’s disease monocytes. Front. Cell. Neurosci. 16, 892899 (2022).
pubmed: 35755775
pmcid: 9229349
doi: 10.3389/fncel.2022.892899
Petropoulou-Vathi, L. et al. Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts. NPJ Parkinsons Dis. 8, 73 (2022).
pubmed: 35676398
pmcid: 9177829
doi: 10.1038/s41531-022-00336-5
Melachroinou, K. et al. Elevated in vitro kinase activity in peripheral blood mononuclear cells of leucine-rich repeat kinase 2 G2019S carriers: a novel enzyme-linked immunosorbent assay-based method. Mov. Disord. 35, 2095–2100 (2020).
pubmed: 32652692
pmcid: 7754308
doi: 10.1002/mds.28175
Bonet-Ponce, L. & Cookson, M. R. LRRK2 recruitment, activity, and function in organelles. FEBS J. 289, 6871–6890 (2022).
pubmed: 34196120
doi: 10.1111/febs.16099
Alcalay, R. N. et al. Higher urine bis(Monoacylglycerol)phosphate levels in LRRK2 G2019S mutation carriers: implications for therapeutic development. Mov. Disord. 35, 134–141 (2020).
doi: 10.1002/mds.27818
Jennings, D. et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci. Transl. Med. 14, eabj2658 (2022).
pubmed: 35675433
doi: 10.1126/scitranslmed.abj2658
Jennings, D. et al. LRRK2 inhibition by BIIB122 in healthy participants and patients with Parkinson’s disease. Mov. Disord. 38, 386–398 (2023).
pubmed: 36807624
doi: 10.1002/mds.29297
Fraser, K. B. et al. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov. Disord. 31, 1543–1550 (2016).
pubmed: 27297049
pmcid: 5053851
doi: 10.1002/mds.26686
Fraser, K. B., Moehle, M. S., Alcalay, R. N., West, A. B. & Consortium, L. C. Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers. Neurology 86, 994–999 (2016).
pubmed: 26865512
pmcid: 4799717
doi: 10.1212/WNL.0000000000002436
Wang, S., Kelly, K., Brotchie, J. M., Koprich, J. B. & West, A. B. Exosome markers of LRRK2 kinase inhibition. NPJ Parkinsons Dis. 6, 32 (2020).
pubmed: 33298972
pmcid: 7666125
doi: 10.1038/s41531-020-00138-7
Taymans, J. M. et al. Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson’s disease and pharmacodynamic biomarkers. NPJ Parkinsons Dis. 9, 21 (2023).
pubmed: 36750568
pmcid: 9905493
doi: 10.1038/s41531-023-00445-9
Virreira Winter, S. et al. Urinary proteome profiling for stratifying patients with familial Parkinson’s disease. EMBO Mol. Med. 13, e13257 (2021).
pmcid: 7933820
doi: 10.15252/emmm.202013257
Rivero-Rios, P. et al. The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A. J. Biol. Chem. 294, 4738–4758 (2019).
pmcid: 6442034
doi: 10.1074/jbc.RA118.005008
Rivero-Rios, P., Romo-Lozano, M., Fernandez, B., Fdez, E. & Hilfiker, S. Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations. Cells https://doi.org/10.3390/cells9071719 (2020).
Dhekne, H. S. et al. A pathway for Parkinson’s Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. Elife https://doi.org/10.7554/eLife.40202 (2018).
Lara Ordonez, A. J. et al. The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization. Biol. Open https://doi.org/10.1242/bio.059468 (2022).
Fdez, E. et al. Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement. iScience 25, 104476 (2022).
pubmed: 35721463
pmcid: 9198432
doi: 10.1016/j.isci.2022.104476
Lara Ordonez, A. J. et al. RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits. Hum. Mol. Genet. 28, 3552–3568 (2019).
pmcid: 6927464
doi: 10.1093/hmg/ddz201
Khan, S. S. et al. Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain. Elife https://doi.org/10.7554/eLife.67900 (2021).
Barrera, J. A. et al. CDK5RAP2 regulates centriole engagement and cohesion in mice. Dev. Cell 18, 913–926 (2010).
pubmed: 20627074
pmcid: 3078807
doi: 10.1016/j.devcel.2010.05.017
Graser, S., Stierhof, Y. D. & Nigg, E. A. Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion. J. Cell Sci. 120, 4321–4331 (2007).
pubmed: 18042621
doi: 10.1242/jcs.020248
Mayor, T., Stierhof, Y. D., Tanaka, K., Fry, A. M. & Nigg, E. A. The centrosomal protein C-Nap1 is required for cell cycle-regulated centrosome cohesion. J. Cell Biol. 151, 837–846 (2000).
pubmed: 11076968
pmcid: 2169446
doi: 10.1083/jcb.151.4.837
Mahen, R. cNap1 bridges centriole contact sites to maintain centrosome cohesion. PLoS Biol. 20, e3001854 (2022).
pmcid: 9595518
doi: 10.1371/journal.pbio.3001854
Hannaford, M. R. et al. Pericentrin interacts with Kinesin-1 to drive centriole motility. J. Cell Biol. https://doi.org/10.1083/jcb.202112097 (2022).
Dang, H. & Schiebel, E. Emerging roles of centrosome cohesion. Open Biol. 12, 220229 (2022).
pubmed: 36285440
pmcid: 9597181
doi: 10.1098/rsob.220229
Madero-Perez, J. et al. Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation. Mol. Neurodegener. 13, 3 (2018).
pubmed: 29357897
pmcid: 5778812
doi: 10.1186/s13024-018-0235-y
Fernandez, B. et al. Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson’s disease patients. Biochem. J. 476, 2797–2813 (2019).
pubmed: 31527116
doi: 10.1042/BCJ20190315
Bonet-Ponce, L. et al. LRRK2 mediates tubulation and vesicle sorting from lysosomes. Sci. Adv. https://doi.org/10.1126/sciadv.abb2454 (2020).
Herbst, S. et al. LRRK2 activation controls the repair of damaged endomembranes in macrophages. EMBO J. 39, e104494 (2020).
pubmed: 32643832
pmcid: 7507578
doi: 10.15252/embj.2020104494
Kalogeropulou, A. F. et al. Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. Biochem. J. 477, 4397–4423 (2020).
pubmed: 33135724
doi: 10.1042/BCJ20200458
Lautier, C. et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am. J. Hum. Genet. 82, 822–833 (2008).
pubmed: 18358451
pmcid: 2427211
doi: 10.1016/j.ajhg.2008.01.015
Saini, P. et al. Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson’s disease. Neurobiol. Aging 100, 119 e117–119 e113 (2021).
doi: 10.1016/j.neurobiolaging.2020.10.019
Lesage, S. et al. Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum. Mol. Genet. 20, 202–210 (2011).
pubmed: 20947659
doi: 10.1093/hmg/ddq454
Wainszelbaum, M. J. et al. The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking. J. Biol. Chem. 283, 13233–13242 (2008).
pubmed: 18319245
pmcid: 2442359
doi: 10.1074/jbc.M800234200
Shi, C. H. et al. NOTCH2NLC intermediate-length repeat expansions are associated with Parkinson disease. Ann. Neurol. 89, 182–187 (2021).
doi: 10.1002/ana.25925
Liu, P. et al. The role of NOTCH2NLC in Parkinson’s disease: a clinical, neuroimaging, and pathological study. Eur. J. Neurol. 29, 1610–1618 (2022).
pubmed: 35147270
doi: 10.1111/ene.15283
Popesco, M. C. et al. Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains. Science 313, 1304–1307 (2006).
pubmed: 16946073
doi: 10.1126/science.1127980
Fiddes, I. T., Pollen, A. A., Davis, J. M. & Sikela, J. M. Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution. Hum. Genet. 138, 715–721 (2019).
pmcid: 6611739
doi: 10.1007/s00439-019-02018-4
Ju, X. C. et al. The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice. Elife https://doi.org/10.7554/eLife.18197 (2016).
Hou, Q. Q., Xiao, Q., Sun, X. Y., Ju, X. C. & Luo, Z. G. TBC1D3 promotes neural progenitor proliferation by suppressing the histone methyltransferase G9a. Sci. Adv. https://doi.org/10.1126/sciadv.aba8053 (2021).
Suzuki, I. K. et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through delta/notch regulation. Cell 173, 1370–1384 e1316 (2018).
pubmed: 29856955
pmcid: 6092419
doi: 10.1016/j.cell.2018.03.067
Keeney, J. G. et al. DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates. Brain Struct. Funct. 220, 3053–3060 (2015).
pubmed: 24957859
doi: 10.1007/s00429-014-0814-9
Fdez, E. et al. Protocol to measure centrosome cohesion deficits mediated by pathogenic LRRK2 in cultured cells using confocal microscopy. STAR Protoc. 4, 102024 (2023).
pubmed: 36856766
pmcid: 9860150
doi: 10.1016/j.xpro.2022.102024
Autissier, P., Soulas, C., Burdo, T. H. & Williams, K. C. Evaluation of a 12-color flow cytometry panel to study lymphocyte, monocyte, and dendritic cell subsets in humans. Cytometry A 77, 410–419 (2010).
pubmed: 20099249
doi: 10.1002/cyto.a.20859
Kluss, J. H. et al. Preclinical modeling of chronic inhibition of the Parkinson’s disease associated kinase LRRK2 reveals altered function of the endolysosomal system in vivo. Mol. Neurodegener. 16, 17 (2021).
pmcid: 7977595
doi: 10.1186/s13024-021-00441-8
Kluss, J. H. et al. Lysosomal positioning regulates Rab10 phosphorylation at LRRK2. Proc. Natl. Acad. Sci. USA 119, e2205492119 (2022).
pmcid: 9618077
doi: 10.1073/pnas.2205492119
Verde, I. et al. Myomegalin is a novel protein of the Golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J. Biol. Chem. 276, 11189–11198 (2001).
pubmed: 11134006
doi: 10.1074/jbc.M006546200
Roubin, R. et al. Myomegalin is necessary for the formation of centrosomal and Golgi-derived microtubules. Biol. Open 2, 238–250 (2013).
pubmed: 23430395
doi: 10.1242/bio.20123392
Peng, H. et al. Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome. Mol. Biol. Cell 32, 1807–1817 (2021).
pmcid: 8684712
doi: 10.1091/mbc.E21-02-0064
Watanabe, K., Takao, D., Ito, K. K., Takahashi, M. & Kitagawa, D. The Cep57-pericentrin module organizes PCM expansion and centriole engagement. Nat. Commun. 10, 931 (2019).
pubmed: 30804344
pmcid: 6389942
doi: 10.1038/s41467-019-08862-2
Kluss, J. H., Bonet-Ponce, L., Lewis, P. A. & Cookson, M. R. Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment. Neurobiol. Dis. 170, 105769 (2022).
pubmed: 35580815
pmcid: 9665168
doi: 10.1016/j.nbd.2022.105769
Boecker, C. A., Goldsmith, J., Dou, D., Cajka, G. G. & Holzbaur, E. L. F. Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Curr. Biol. 31, 2140–2154 e2146 (2021).
pubmed: 33765413
pmcid: 8154747
doi: 10.1016/j.cub.2021.02.061
Douanne, T., Stinchcombe, J. C. & Griffiths, G. M. Teasing out function from morphology: Similarities between primary cilia and immune synapses. J. Cell Biol. https://doi.org/10.1083/jcb.202102089 (2021).
Delecluse, H. J., Bartnizke, S., Hammerschmidt, W., Bullerdiek, J. & Bornkamm, G. W. Episomal and integrated copies of Epstein-Barr virus coexist in Burkitt lymphoma cell lines. J. Virol. 67, 1292–1299 (1993).
pmcid: 237496
doi: 10.1128/jvi.67.3.1292-1299.1993
Tzellos, S. & Farrell, P. J. Epstein-barr virus sequence variation-biology and disease. Pathogens 1, 156–174 (2012).
pubmed: 25436768
pmcid: 4235690
doi: 10.3390/pathogens1020156
Gonzalez-Hunt, C. P. et al. Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease. Sci. Rep. 10, 17293 (2020).
pubmed: 33057100
pmcid: 7557909
doi: 10.1038/s41598-020-74195-6
Howlett, E. H. et al. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson’s disease. Hum. Mol. Genet. 26, 4340–4351 (2017).
pubmed: 28973664
pmcid: 5886254
doi: 10.1093/hmg/ddx320
Qi, R. et al. A blood-based marker of mitochondrial DNA damage in Parkinson’s disease. Sci. Transl. Med. 15, eabo1557 (2023).
pubmed: 37647388
doi: 10.1126/scitranslmed.abo1557
Sanders, L. H. et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: reversal by gene correction. Neurobiol. Dis. 62, 381–386 (2014).
pubmed: 24148854
doi: 10.1016/j.nbd.2013.10.013
Kozina, E., Byrne, M. & Smeyne, R. J. Mutant LRRK2 in lymphocytes regulates neurodegeneration via IL-6 in an inflammatory model of Parkinson’s disease. NPJ Parkinsons Dis. 8, 24 (2022).
pubmed: 35292674
pmcid: 8924242
doi: 10.1038/s41531-022-00289-9
Louie, L. G. & King, M. C. A novel approach to establishing permanent lymphoblastoid cell lines: Epstein-Barr virus transformation of cryopreserved lymphocytes. Am. J. Hum. Genet. 48, 637–638 (1991).
pubmed: 1847792
pmcid: 1682991
Kedariti, M. et al. LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease. NPJ Parkinsons Dis. 8, 92 (2022).
pubmed: 35853899
pmcid: 9296523
doi: 10.1038/s41531-022-00354-3
Dobson-Stone, C. et al. CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis. Brain 143, 783–799 (2020).
pubmed: 32185393
pmcid: 7089666
doi: 10.1093/brain/awaa039
Guo, M. H., Plummer, L., Chan, Y. M., Hirschhorn, J. N. & Lippincott, M. F. Burden testing of rare variants identified through exome sequencing via publicly available control data. Am. J. Hum. Genet. 103, 522–534 (2018).
pmcid: 6174288
doi: 10.1016/j.ajhg.2018.08.016