Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with GBA1 Mutations

Abstract

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.

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

“…Furthermore, PIT1 co-localized with TXNDC5 is required for ER homeostasis, chondrocyte survival, and skeletal development [197], also TXNDC5 knockdown is highly toxic to osteosarcoma cells, possibly implying that it has a critical function in cells that endogenously express collagen-I [198]. Other studies have identified an upregulation of TXNDC5 in Parkinson's disease, respiratory distress syndrome following cardiopulmonary bypass, COVID-19, malaria, Salmonella enteritidis and Marek's disease infection [199][200][201][202][203][204]. However, TNFRSF17 and TXNDC5 are the target genes for the COVID-19 vaccine [205].…”