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

Cell Rep. 2023 Mar 28;42(3):112180. doi: 10.1016/j.celrep.2023.112180. Epub 2023 Mar 3.


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.

Keywords: CP: Neuroscience; Parkinson’s; glucocerebrosidase; glycosylation; iPSC; lysosome; neuritogenesis; phosphoproteomics; post-translational modifications; proteomics; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dopaminergic Neurons / metabolism
  • Glucosylceramidase / genetics
  • Glucosylceramidase / metabolism
  • Humans
  • Mutation
  • Neuronal Outgrowth
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Protein Processing, Post-Translational
  • Proteomics


  • Glucosylceramidase
  • GBA protein, human