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Abstract The prevalence of Parkinson’s disease (PD) is increasing because of the aging population. Early diagnosis and prognosis of PD remain challenging, suggesting that seeking appropriate biomarkers for PD is crucial. GPNMB and Alpha-synuclein (α-syn) have been reported to contribute to PD pathogenesis and are correlated with PD onset and disease progression. We utilized Mendelian Randomization (MR) analysis to elucidate the association of GPNMB and α-syn with PD and its disease progression. Five MR methods were employed, and inverse variance weighted was chosen as the primary method. The results of MR analysis showed that cerebrospinal fluid (CSF) α-syn correlated with the Unified Parkinson's Disease Rating Scale Ⅲ (UPDRS Ⅲ) and Hoehn and Yahr (H&Y) stage, and plasma α-syn was associated with H&Y stage at baseline suggestively, indicating that α-syn is a promising biomarker for motor symptoms of PD. Overall, CSF and plasma α-syn are potential biomarkers for predicting PD motor symptoms, which warrant further studies. However, no association was detected between GPNMB and PD risk or disease progression.
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