Abstract
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.
Originalsprog | Engelsk |
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Artikelnummer | 112180 |
Tidsskrift | Cell Reports |
Vol/bind | 42 |
Udgave nummer | 3 |
Antal sider | 26 |
ISSN | 2211-1247 |
DOI | |
Status | Udgivet - 28. mar. 2023 |
Bibliografisk note
Funding Information:The work was funded by the Monument Trust Discovery Award (J-1403) from Parkinson's UK. H.B. and M.M. are funded by the Lundbeck Foundation (R167-2013-15778), the Jascha Foundation (3687, 5611), the Danish Parkinson Foundation, and Innovation Fund Denmark (BrainStem, 4108-00008B). P.K. is funded by a studentship from the Medical Research Council (MRC) UK. The James Martin Stem Cell Facility, University of Oxford, is financially supported by the Wellcome Trust WTISSF121302, the Oxford Martin School LC0910-004 (S.A.C.), and the MRC Dementias Platform UK Stem Cell Network Capital Equipment (MR/M024962/1) and Partnership Awards (MR/N013255/1) (S.A.C. and R.W.-M.). We thank the High-Throughput Genomics Group at the Wellcome Trust Center for Human Genetics, Oxford (funded by Wellcome Trust grant ref. 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of Illumina genotyping and transcriptome data. The Villum Center for Bioanalytical Sciences at the University of Southern Denmark is acknowledged for access to state-of-the-art mass spectrometric instrumentation. The graphical abstract is created with BioRender.com. Conceptualization, H.B. B.J.R. M.R.L. and R.W.-M.; methodology, H.B. B.J.R. M.R.L. S.A.C. and R.W.-M.; software, M.B.B. P.K. and J.P.C.; formal analysis, H.B. B.J.R. P.J. and R.H.R.; investigation, H.B. B.J.R. P.J. S.I.S. D.L.E.V. L.N.K. U.C. M.C.C. W.M. R.M.-G. F.S.B. J.B. H.J.R.F. and J.V.; resources, T.M.C. S.A.C. M.R.L. and R.W.-M.; writing – original draft, H.B.; writing – review & editing, H.B. B.J.R. P.J. S.A.C. M.M. M.R.L. and R.W.-M.; visualization, H.B. B.J.R. R.H.R. and S.A.C.; supervision, B.J.R. M.M. M.R.L. and R.W.-M.; funding acquisition, H.B. S.A.C. M.M. M.R.L. and R.W.-M. The authors’ current additional affiliations, unrelated to this work, are as follows: D.L.E.V. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; L.N.K. Nature Reviews Neurology, London, UK; U.C. School of Medicine, Cardiff University, Cardiff, UK; F.S.B. School of Biological Sciences, University of Edinburgh, Edinburgh, UK; J.B. Clinical Neurosciences, University of Cambridge, Cambridge, UK; J.P.C. Astbury Center for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, UK; and T.M.C. Mend the Gap, University of British Columbia, Vancouver, BC, Canada. We support inclusive, diverse, and equitable conduct of research.
Funding Information:
The work was funded by the Monument Trust Discovery Award (J-1403) from Parkinson's UK . H.B. and M.M. are funded by the Lundbeck Foundation (R167-2013-15778) , the Jascha Foundation (3687, 5611) , the Danish Parkinson Foundation , and Innovation Fund Denmark (BrainStem, 4108-00008B ). P.K. is funded by a studentship from the Medical Research Council (MRC) UK. The James Martin Stem Cell Facility , University of Oxford , is financially supported by the Wellcome Trust WTISSF121302 , the Oxford Martin School LC0910-004 (S.A.C.), and the MRC Dementias Platform UK Stem Cell Network Capital Equipment ( MR/M024962/1 ) and Partnership Awards ( MR/N013255/1 ) (S.A.C. and R.W.-M.). We thank the High-Throughput Genomics Group at the Wellcome Trust Center for Human Genetics, Oxford (funded by Wellcome Trust grant ref. 090532/Z/09/Z and MRC Hub grant G0900747 91070 ) for the generation of Illumina genotyping and transcriptome data. The Villum Center for Bioanalytical Sciences at the University of Southern Denmark is acknowledged for access to state-of-the-art mass spectrometric instrumentation. The graphical abstract is created with BioRender.com .
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