Proteomic analysis of GBA iPSC-dopamine neurons

Heterozygous mutations in the glucocerebrosidase gene (GBA) are the strongest common genetic risk factors for Parkinson’s disease (PD) present in around 5-10% of PD patients, resulting in lower age of onset and exacerbating disease progression, including an increased risk of dementia. However, the exact mechanisms leading from dysfunction of the enzyme glucocerebrosidase (GCase) encoded by GBA to PD pathogenesis and neurodegeneration remain unclear. Applying a novel multi-part enrichment workflow we have developed, we have isolated and quantified peptides with phosphorylation, cysteine-modification or N-linked glycosylation simultaneously. We applied this methodology to iPSC-derived dopaminergic neurons from GBA-N370S PD patients and healthy age-matched controls, identifying large numbers of dysregulated native and modified proteins.