The S-adenosylhomocysteine (SAH) hydrolyzing enzyme AHCY functionally links the circadian clock to methionine metabolism.

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder affecting over 1% of the 65 + age population. Saposin C, a lysosomal protein required for the normal activity of glucocerebrosidase (GCase), may serve as a disease modifier in PD. Saposin C is cleaved from its precursor, Prosaposin (PSAP), which is secreted as an uncleaved protein and exerts neuroprotective effects. In this study, we aim to elucidate the neuroprotective roles of PSAP and saposin C in PD by evaluating their effects on α-synuclein accumulation in human neuroblastoma cells. Stable overexpression of PSAP reduced monomeric α-synuclein levels in SH-SY5Y cells, while PSAP knockdown by small interfering RNA led to the opposite effect, and those effects were independent of GCase activity. Autophagy flux was decreased by stable PSAP overexpression. Furthermore, a flow-through assay revealed that recombinant saposin C was able to detach α-synuclein from artificial glucosylceramide-enriched lipid membranes at the lysosomal pH. Taken together, our findings provide further evidence that PSAP and saposin C as key proteins involved in α-synuclein clearance by dislodging it from lipid membranes.

Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.