Deficiency of SCAMP5 causes Parkinson's disease due to loss of dopamine neurons.

Parkinson's disease is a progressive neurodegenerative disorder characterized by symptoms such as bradykinesia, resting tremors, and muscle rigidity. Although several disease-causing genes of juvenile Parkinson's disease have been reported, the underlying mechanism remains unclear. Here, we identified SCAMP5 as a novel disease-causing gene of Parkinson's disease in a consanguineous family with juvenile Parkinson's disease. Functional studies in PC12 cell lines revealed that SCAMP5 deficiency increased the level of α-synuclein protein and α-synuclein oligomers, leading to increased cell apoptosis and decreased dopamine secretion. SCAMP5 knockdown in SH-SY5Y cells reduces α-synuclein secretion via exosome. Expression of human wild-type SCAMP5 rescued these effects, whereas the R91W mutant SCAMP5 did not. Scamp5a knockout zebrafish showed Parkinson's disease-like phenotypes, including bradykinesia, loss of dopamine neurons and decreased dopamine content in the brain. Transcriptome analysis unveiled upregulated JNK signaling in scamp5a knockout zebrafish, contributing to neuronal apoptosis. Importantly, human SCAMP5 prevented both dopamine neuron loss and bradykinesia in scamp5a knockout zebrafish, suggesting its therapeutic potential in Parkinson's disease. Overall, our findings identify SCAMP5 as a novel disease-causing gene of Parkinson's disease and highlight its neuroprotective role, opening new avenues for Parkinson's disease treatment.