Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
24 03 2022
24 03 2022
Historique:
received:
25
08
2021
accepted:
25
02
2022
revised:
21
02
2022
entrez:
24
3
2022
pubmed:
25
3
2022
medline:
13
4
2022
Statut:
epublish
Résumé
Mutations in N-glycanase 1 (NGLY1), which deglycosylates misfolded glycoproteins for degradation, can cause NGLY1 deficiency in patients and their abnormal fetal development in multiple organs, including microcephaly and other neurological disorders. Using cerebral organoids (COs) developed from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), we investigate how NGLY1 dysfunction disturbs early brain development. While NGLY1 loss had limited impact on the undifferentiated cells, COs developed from NGLY1-deficient hESCs showed defective formation of SATB2-positive upper-layer neurons, and attenuation of STAT3 and HES1 signaling critical for sustaining radial glia. Bulk and single-cell transcriptomic analysis revealed premature neuronal differentiation accompanied by downregulation of secreted and transcription factors, including TTR, IGFBP2, and ID4 in NGLY1-deficient COs. NGLY1 malfunction also dysregulated ID4 and enhanced neuronal differentiation in CO transplants developed in vivo. NGLY1-deficient CO cells were more vulnerable to multiple stressors; treating the deficient cells with recombinant TTR reduced their susceptibility to stress from proteasome inactivation, likely through LRP2-mediated activation of MAPK signaling. Expressing NGLY1 led to IGFBP2 and ID4 upregulation in CO cells developed from NGLY1-deficiency patient's hiPSCs. In addition, treatment with recombinant IGFBP2 enhanced ID4 expression, STAT3 signaling, and proliferation of NGLY1-deficient CO cells. Overall, our discoveries suggest that dysregulation of stress responses and neural precursor differentiation underlies the brain abnormalities observed in NGLY1-deficient individuals.
Identifiants
pubmed: 35322011
doi: 10.1038/s41419-022-04693-0
pii: 10.1038/s41419-022-04693-0
pmc: PMC8942998
doi:
Substances chimiques
Glycoproteins
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
NGLY1 protein, human
EC 3.5.1.52
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
EC 3.5.1.52
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
262Subventions
Organisme : NIA NIH HHS
ID : T32 AG020494
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121293
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Huang C, Harada Y, Hosomi A, Masahara-Negishi Y, Seino J, Fujihira H, et al. Endo-beta-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells. Proc Natl Acad Sci USA. 2015;112:1398–403.
pubmed: 25605922
pmcid: 4321286
doi: 10.1073/pnas.1414593112
Caglayan AO, Comu S, Baranoski JF, Parman Y, Kaymakcalan H, Akgumus GT, et al. NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy. Eur J Med Genet. 2015;58:39–43.
pubmed: 25220016
doi: 10.1016/j.ejmg.2014.08.008
Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353–61.
pubmed: 22581936
doi: 10.1136/jmedgenet-2012-100819
Suzuki T. The cytoplasmic peptide:N-glycanase (Ngly1)-basic science encounters a human genetic disorder. J Biochem. 2015;157:23–34.
pubmed: 25398991
doi: 10.1093/jb/mvu068
Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014;16:751–8.
pubmed: 24651605
pmcid: 4243708
doi: 10.1038/gim.2014.22
Lam C, Ferreira C, Krasnewich D, Toro C, Latham L, Zein WM, et al. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med. 2017;19:160–8.
pubmed: 27388694
doi: 10.1038/gim.2016.75
Might M, Wilsey M. The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated. Genet Med. 2014;16:736–7.
pubmed: 24651604
doi: 10.1038/gim.2014.23
Kariminejad A, Shakiba M, Shams M, Namiranian P, Eghbali M, Talebi S, et al. NGLY1 deficiency: Novel variants and literature review. Eur J Med Genet. 2021;64:104146.
pubmed: 33497766
doi: 10.1016/j.ejmg.2021.104146
Asahina M, Fujinawa R, Nakamura S, Yokoyama K, Tozawa R, Suzuki T. Ngly1 -/- rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems. Hum Mol Genet. 2020;29:1635–47.
pubmed: 32259258
pmcid: 7322575
doi: 10.1093/hmg/ddaa059
Habibi-Babadi N, Su A, de Carvalho CE, Colavita A. The N-glycanase png-1 acts to limit axon branching during organ formation in Caenorhabditis elegans. J Neurosci. 2010;30:1766–76.
pubmed: 20130186
pmcid: 6634002
doi: 10.1523/JNEUROSCI.4962-08.2010
Rodriguez TP, Mast JD, Hartl T, Lee T, Sand P, Perlstein EO. Defects in the neuroendocrine axis contribute to global development delay in a Drosophila model of NGLY1 deficiency. G3. 2018;8:2193–204.
pubmed: 29735526
pmcid: 6027897
doi: 10.1534/g3.118.300578
Galeone A, Han SY, Huang C, Hosomi A, Suzuki T, Jafar-Nejad H. Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1. eLife. 2017;6:e27612.
pubmed: 28826503
pmcid: 5599231
doi: 10.7554/eLife.27612
Owings KG, Lowry JB, Bi Y, Might M, Chow CY. Transcriptome and functional analysis in a Drosophila model of NGLY1 deficiency provides insight into therapeutic approaches. Hum Mol Genet. 2018;27:1055–66.
pubmed: 29346549
pmcid: 5886220
doi: 10.1093/hmg/ddy026
Tomlin FM, Gerling-Driessen UIM, Liu YC, Flynn RA, Vangala JR, Lentz CS, et al. Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity. ACS Cent Sci. 2017. https://doi.org/10.1021/acscentsci.1027b00224.
Yang K, Huang R, Fujihira H, Suzuki T, Yan N. N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1. J Exp Med. 2018;215:2600–16.
pubmed: 30135079
pmcid: 6170171
doi: 10.1084/jem.20180783
Zolekar A, Lin VJT, Mishra NM, Ho YY, Hayatshahi HS, Parab A, et al. Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1. Br J Cancer. 2018;119:1538–51.
pubmed: 30385822
pmcid: 6288164
doi: 10.1038/s41416-018-0265-9
Fujihira H, Masahara-Negishi Y, Tamura M, Huang C, Harada Y, Wakana S, et al. Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene. PLoS Genet. 2017;13:e1006696.
pubmed: 28426790
pmcid: 5398483
doi: 10.1371/journal.pgen.1006696
Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Brauninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA. 2015;112:15672–7.
pubmed: 26644564
pmcid: 4697386
doi: 10.1073/pnas.1520760112
Bershteyn M, Nowakowski TJ, Pollen AA, Di Lullo E, Nene A, Wynshaw-Boris A, et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell. 2017;20:435–49 e434.
pubmed: 28111201
pmcid: 5667944
doi: 10.1016/j.stem.2016.12.007
Dakic V, Minardi Nascimento J, Costa Sartore R, Maciel RM, de Araujo DB, Ribeiro S, et al. Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Sci Rep. 2017;7:12863.
pubmed: 28993683
pmcid: 5634411
doi: 10.1038/s41598-017-12779-5
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.
pubmed: 23995685
doi: 10.1038/nature12517
Lee CT, Chen J, Kindberg AA, Bendriem RM, Spivak CE, Williams MP, et al. CYP3A5 mediates effects of cocaine on human neocorticogenesis: studies using an in vitro 3D self-organized hPSC model with a single cortex-like unit. Neuropsychopharmacology. 2017;42:774–84.
pubmed: 27534267
doi: 10.1038/npp.2016.156
Pasca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12:671–8.
pubmed: 26005811
pmcid: 4489980
doi: 10.1038/nmeth.3415
Pollen AA, Bhaduri A, Andrews MG, Nowakowski TJ, Meyerson OS, Mostajo-Radji MA, et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell. 2019;176:743–56 e717.
pubmed: 30735633
pmcid: 6544371
doi: 10.1016/j.cell.2019.01.017
Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570:523–7.
pubmed: 31168097
pmcid: 6906116
doi: 10.1038/s41586-019-1289-x
Watanabe M, Buth JE, Vishlaghi N, de la Torre-Ubieta L, Taxidis J, Khakh BS, et al. Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep. 2017;21:517–32.
pubmed: 29020636
pmcid: 5637483
doi: 10.1016/j.celrep.2017.09.047
Zhang W, Yang SL, Yang M, Herrlinger S, Shao Q, Collar JL, et al. Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in neural progenitors. Nat Commun. 2019;10:2612.
pubmed: 31197141
pmcid: 6565620
doi: 10.1038/s41467-019-10497-2
Trujillo CA, Muotri AR. Brain organoids and the study of neurodevelopment. Trends Mol Med. 2018;24:982–90.
pubmed: 30377071
pmcid: 6289846
doi: 10.1016/j.molmed.2018.09.005
Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Min Yang S, Berger DR, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature. 2017;545:48–53.
pubmed: 28445462
pmcid: 5659341
doi: 10.1038/nature22047
Kanton S, Boyle MJ, He Z, Santel M, Weigert A, Sanchis-Calleja F, et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature. 2019;574:418–22.
pubmed: 31619793
doi: 10.1038/s41586-019-1654-9
Wang YC, Nakagawa M, Garitaonandia I, Slavin I, Altun G, Lacharite RM, et al. Specific lectin biomarkers for isolation of human pluripotent stem cells identified through array-based glycomic analysis. Cell Res. 2011;21:1551–63.
pubmed: 21894191
pmcid: 3364725
doi: 10.1038/cr.2011.148
Lin VJT, Hu J, Yan L-J, Zolekar A, Wang Y-C. Urine sample-derived cerebral organoids suitable for studying neurodevelopment and pharmacological responses. Front Cell Dev Biol. 2020;8:304.
pubmed: 32528947
pmcid: 7247822
doi: 10.3389/fcell.2020.00304
Susaki EA, Tainaka K, Perrin D, Yukinaga H, Kuno A, Ueda HR. Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging. Nat Protoc. 2015;10:1709–27.
pubmed: 26448360
doi: 10.1038/nprot.2015.085
Muller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, et al. A bioinformatic assay for pluripotency in human cells. Nat Methods. 2011;8:315–7.
pubmed: 21378979
pmcid: 3265323
doi: 10.1038/nmeth.1580
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411–20.
pubmed: 29608179
pmcid: 6700744
doi: 10.1038/nbt.4096
Campbell K, Gotz M. Radial glia: multi-purpose cells for vertebrate brain development. Trends Neurosci. 2002;25:235–8.
pubmed: 11972958
doi: 10.1016/S0166-2236(02)02156-2
Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009;32:149–84.
pubmed: 19555289
pmcid: 3086722
doi: 10.1146/annurev.neuro.051508.135600
Malatesta P, Gotz M. Radial glia - from boring cables to stem cell stars. Development. 2013;140:483–6.
pubmed: 23293279
doi: 10.1242/dev.085852
Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem. 2001;276:30467–74.
pubmed: 11399758
doi: 10.1074/jbc.M102420200
Pollen AA, Nowakowski TJ, Chen J, Retallack H, Sandoval-Espinosa C, Nicholas CR, et al. Molecular identity of human outer radial glia during cortical development. Cell. 2015;163:55–67.
pubmed: 26406371
pmcid: 4583716
doi: 10.1016/j.cell.2015.09.004
Zheng X, Boyer L, Jin M, Mertens J, Kim Y, Ma L, et al. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife. 2016;5:e13374.
pubmed: 27282387
pmcid: 4963198
doi: 10.7554/eLife.13374
Khan S. IGFBP-2 signaling in the brain: from brain development to higher order brain functions. Front Endocrinol. 2019;10:822.
doi: 10.3389/fendo.2019.00822
Li T, Forbes ME, Fuller GN, Li J, Yang X, Zhang W. IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene. 2020;39:2243–57.
pubmed: 31925333
pmcid: 7347283
doi: 10.1038/s41388-020-1154-2
Shen F, Song C, Liu Y, Zhang J, Wei Song S. IGFBP2 promotes neural stem cell maintenance and proliferation differentially associated with glioblastoma subtypes. Brain Res. 2019;1704:174–86.
pubmed: 30347220
doi: 10.1016/j.brainres.2018.10.018
Bedford L, Walker R, Kondo T, van Cruchten I, King ER, Sablitzky F. Id4 is required for the correct timing of neural differentiation. Developmental Biol. 2005;280:386–95.
doi: 10.1016/j.ydbio.2005.02.001
Yun K, Mantani A, Garel S, Rubenstein J, Israel MA. Id4 regulates neural progenitor proliferation and differentiation in vivo. Development. 2004;131:5441–8.
pubmed: 15469968
doi: 10.1242/dev.01430
Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018;19:365–81.
pubmed: 29626215
pmcid: 6399518
doi: 10.1038/s41580-018-0001-6
Sandy Z, da Costa IC, Schmidt CK. More than meets the ISG15: emerging roles in the DNA damage response and beyond. Biomolecules. 2020;10:1557.
pmcid: 7698331
doi: 10.3390/biom10111557
Gomes JR, Nogueira RS, Vieira M, Santos SD, Ferraz-Nogueira JP, Relvas JB, et al. Transthyretin provides trophic support via megalin by promoting neurite outgrowth and neuroprotection in cerebral ischemia. Cell Death Differ. 2016;23:1749–64.
pubmed: 27518433
pmcid: 5071567
doi: 10.1038/cdd.2016.64
Rauscher B, Mueller WF, Clauder-Munster S, Jakob P, Islam MS, Sun H, et al. Patient-derived gene and protein expression signatures of NGLY1 deficiency. J Biochem. 2021, https://doi.org/10.1093/jb/mvab131 .
Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, et al. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell. 2011;8:59–71.
pubmed: 21211782
pmcid: 3018289
doi: 10.1016/j.stem.2010.11.028
Aldred AR, Brack CM, Schreiber G. The cerebral expression of plasma protein genes in different species. Comp Biochem Physiol B Biochem Mol Biol. 1995;111:1–15.
pubmed: 7749630
doi: 10.1016/0305-0491(94)00229-N
Oliveira SM, Cardoso I, Saraiva MJ. Transthyretin: roles in the nervous system beyond thyroxine and retinol transport. Expert Rev Endocrinol Metab. 2012;7:181–9.
pubmed: 30764010
doi: 10.1586/eem.12.2
Santos SD, Lambertsen KL, Clausen BH, Akinc A, Alvarez R, Finsen B, et al. CSF transthyretin neuroprotection in a mouse model of brain ischemia. J Neurochem. 2010;115:1434–44.
pubmed: 21044072
doi: 10.1111/j.1471-4159.2010.07047.x
Buxbaum JN, Ye Z, Reixach N, Friske L, Levy C, Das P, et al. Transthyretin protects Alzheimer’s mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci USA. 2008;105:2681–6.
pubmed: 18272491
pmcid: 2268196
doi: 10.1073/pnas.0712197105
Silva CS, Eira J, Ribeiro CA, Oliveira A, Sousa MM, Cardoso I, et al. Transthyretin neuroprotection in Alzheimer’s disease is dependent on proteolysis. Neurobiol Aging. 2017;59:10–14.
pubmed: 28780366
doi: 10.1016/j.neurobiolaging.2017.07.002
Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci. 2002;22:7380–8.
pubmed: 12196559
pmcid: 6758007
doi: 10.1523/JNEUROSCI.22-17-07380.2002
Stein TD, Anders NJ, DeCarli C, Chan SL, Mattson MP, Johnson JA. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J Neurosci. 2004;24:7707–17.
pubmed: 15342738
pmcid: 6729623
doi: 10.1523/JNEUROSCI.2211-04.2004
Monk JA, Sims NA, Dziegielewska KM, Weiss RE, Ramsay RG, Richardson SJ. Delayed development of specific thyroid hormone-regulated events in transthyretin null mice. Am J Physiol Endocrinol Metab. 2013;304:E23–31.
pubmed: 23092911
doi: 10.1152/ajpendo.00216.2012
Khan S, Lu X, Huang Q, Tang J, Weng J, Yang Z, et al. IGFBP2 plays an essential role in cognitive development during early life. Adv Sci. 2019;6:1901152.
doi: 10.1002/advs.201901152
Eze UC, Bhaduri A, Haeussler M, Nowakowski TJ, Kriegstein AR. Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia. Nat Neurosci. 2021;24:584–94.
pubmed: 33723434
pmcid: 8012207
doi: 10.1038/s41593-020-00794-1
Jen Y, Manova K, Benezra R. Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Dev Dyn. 1996;207:235–52.
pubmed: 8922523
doi: 10.1002/(SICI)1097-0177(199611)207:3<235::AID-AJA1>3.0.CO;2-I
Jen Y, Manova K, Benezra R. Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis. Dev Dyn. 1997;208:92–106.
pubmed: 8989524
doi: 10.1002/(SICI)1097-0177(199701)208:1<92::AID-AJA9>3.0.CO;2-X
Chua CY, Liu Y, Granberg KJ, Hu L, Haapasalo H, Annala MJ, et al. IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene. 2016;35:738–47.
pubmed: 25893308
doi: 10.1038/onc.2015.131
Han S, Li Z, Master LM, Master ZW, Wu A. Exogenous IGFBP-2 promotes proliferation, invasion, and chemoresistance to temozolomide in glioma cells via the integrin beta1-ERK pathway. Br J Cancer. 2014;111:1400–9.
pubmed: 25093489
pmcid: 4183856
doi: 10.1038/bjc.2014.435
Galeone A, Adams JM, Matsuda S, Presa MF, Pandey A, Han SY, et al. Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation. eLife. 2020;9:e55596.
pubmed: 32720893
pmcid: 7394544
doi: 10.7554/eLife.55596
Samanta J, Kessler JA. Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development. 2004;131:4131–42.
pubmed: 15280210
doi: 10.1242/dev.01273
Zhang K, Li L, Huang C, Shen C, Tan F, Xia C, et al. Distinct functions of BMP4 during different stages of mouse ES cell neural commitment. Development. 2010;137:2095–105.
pubmed: 20504958
doi: 10.1242/dev.049494
Bond AM, Bhalala OG, Kessler JA. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev Neurobiol. 2012;72:1068–84.
pubmed: 22489086
pmcid: 3773925
doi: 10.1002/dneu.22022
Tambe MA, Ng BG, Freeze HH. N-glycanase 1 transcriptionally regulates aquaporins independent of its enzymatic activity. Cell Rep. 2019;29:4620–31 e4624.
pubmed: 31875565
doi: 10.1016/j.celrep.2019.11.097