GBA mutation exacerbates α-synuclein pathology with involvement of ROS and p38 MAPK signaling in Parkinson's disease.
GBA mutation exacerbates α-synuclein pathology with involvement of ROS and p38 MAPK signaling in Parkinson's disease.
Where did the research take place?
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Changshu, CN · Author affiliation
Department of Neurology, Changshu Hospital affiliated to Nanjing University of Chinese Medicine, Changshu 215500, China.Location evidence
Nanjing, CN · Author affiliation
Department of Neurology, Changshu Hospital affiliated to Nanjing University of Chinese Medicine, Changshu 215500, China.Location evidence
CN · Author affiliation · country only
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, China.Location evidence
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Original abstract
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.