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초록

Objectives Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by the progressive narrowing of arteries at the base of the brain, forming abnormal collateral vascular networks. While vascular parkinsonism is noted in MMD, its link to Parkinson's disease (PD) has not been explored. We aimed to determine whether the risk of PD is increased in patients with MMD and to identify the potential role of the RNF213 gene. Methods We report two cases of PD with a history of MMD associated with the Arg4810Lys variant of RNF213. Using the Korean National Health Insurance Service database, we studied the association between MMD and subsequent PD risk using Cox proportional hazards regression analysis. Moreover, we explored the interaction between alpha-synuclein and RNF213 proteins by overexpressing SNCA and RNF213 in SH-SY5Y cells. Furthermore, we confirmed the proximity of Lewy pathology and RNF213 proteins in postmortem brain tissues from three patients with PD and age-matched controls. Results Among 16,830 patients aged >= 40 with MMD, 3415 were enrolled, excluding those with prior PD or stroke, along with a matched control group of 33,974. The analysis revealed an increased PD risk in patients with MMD (hazard ratio = 4.45 [3.40-5.82], p < 0.0001). Overexpression of RNF213 resulted in cytoplasmic inclusions, which were worsened by the co-expression of SNCA and the Arg4810Lys variant of RNF213. Histological studies confirmed the co-localization of alpha-synuclein aggregates and RNF213 proteins in PD brain tissues. Interpretation This study confirms the heightened PD risk in patients with MMD and suggests a pathophysiological link through alpha-synuclein and RNF213 interactions.

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