GBA mutation exacerbates α-synuclein pathology with involvement of ROS and p38 MAPK signaling in Parkinson's disease

The glucocerebrosidase (GBA) gene is the second most significant genetic risk factor for Parkinson's disease (PD) pathogenesis. Notably, GBA mutations not only enhance PD susceptibility in the general population but also accelerate disease progression. Nevertheless, the precise molecular mechanisms underlying GBA-associated PD pathogenesis remain elusive. In this study, we demonstrated that the L444P mutation in GBA significantly impairs the enzymatic activity of its encoded protein, glucocerebrosidase (GCase). It caused lysosomal dysfunction and increased α-synuclein (α-syn) expression and aggregation induced by α-syn preformed fibril (PFF). Mechanistically, our data revealed that the L444P GBA mutation increased reactive oxygen species (ROS) levels associated with activation of the p38 MAPK signaling pathway. Importantly, pharmacological inhibition of p38 MAPK pathway can change consistent with altered autophagic degradation and reduce PFF-induced α-syn aggregation, which is exacerbated by the L444P GBA mutation. These findings suggest that inhibiting p38 signaling provides a mechanistic rationale for targeting this pathway in GBA-associated PD.