Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.

Bogetofte H., Ryan BJ., Jensen P., Schmidt SI., Vergoossen DLE., Barnkob MB., Kiani LN., Chughtai U., Heon-Roberts R., Caiazza MC., McGuinness W., Márquez-Gómez R., Vowles J., Bunn FS., Brandes J., Kilfeather P., Connor JP., Fernandes HJR., Caffrey TM., Meyer M., Cowley SA., Larsen MR., Wade-Martins R.

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.

DOI

10.1016/j.celrep.2023.112180

Type

Journal article

Journal

Cell Rep

Publication Date

28/03/2023

Volume

42

Keywords

CP: Neuroscience, Parkinson’s, glucocerebrosidase, glycosylation, iPSC, lysosome, neuritogenesis, phosphoproteomics, post-translational modifications, proteomics, stem cells, Humans, Dopaminergic Neurons, Glucosylceramidase, Mutation, Neuronal Outgrowth, Parkinson Disease, Protein Processing, Post-Translational, Proteomics

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