| Autor: |
Helle Bogetofte, Brent J. Ryan, Pia Jensen, Sissel I. Schmidt, Dana L.E. Vergoossen, Mike B. Barnkob, Lisa N. Kiani, Uroosa Chughtai, Rachel Heon-Roberts, Maria Claudia Caiazza, William McGuinness, Ricardo Márquez-Gómez, Jane Vowles, Fiona S. Bunn, Janine Brandes, Peter Kilfeather, Jack P. Connor, Hugo J.R. Fernandes, Tara M. Caffrey, Morten Meyer, Sally A. Cowley, Martin R. Larsen, Richard Wade-Martins |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 42, Iss 3, Pp 112180- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.112180 |
| Popis: |
Summary: Variants at the GBA locus, encoding glucocerebrosidase, are the strongest common genetic risk factor for Parkinson’s disease (PD). To understand GBA-related disease mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins and PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations in glycosylation status show disturbances in the autophagy-lysosomal pathway, which concur with upstream perturbations in mammalian target of rapamycin (mTOR) activation in GBA-PD neurons. Several native and modified proteins encoded by PD-associated genes are dysregulated in GBA-PD neurons. Integrated pathway analysis reveals impaired neuritogenesis in GBA-PD neurons and identify tau as a key pathway mediator. Functional assays confirm neurite outgrowth deficits and identify impaired mitochondrial movement in GBA-PD neurons. Furthermore, pharmacological rescue of glucocerebrosidase activity in GBA-PD neurons improves the neurite outgrowth deficit. Overall, this study demonstrates the potential of PTMomics to elucidate neurodegeneration-associated pathways and potential drug targets in complex disease models. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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