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Published on: June 23, 2023
Moyamoya Disease and the Risk of Parkinson's Disease
Dallah Yoo1, Jeong-Yong Shin2, Rugyeom Lee3
1Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Republic of Korea.
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 α-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 α-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 α-synuclein and RNF213 interactions.
Insights
Moyamoya disease (MMD) patients face a significantly higher risk of developing Parkinson's disease (PD). This increased risk is linked to interactions between alpha-synuclein and the RNF213 gene, suggesting a shared pathological pathway.
Area of Science:
- Neurology
- Genetics
- Epidemiology
Background:
- Moyamoya disease (MMD) involves progressive narrowing of brain arteries and abnormal vascular networks.
- Vascular parkinsonism is observed in MMD, but its relationship with Parkinson's disease (PD) remains unclear.
- The RNF213 gene is implicated in MMD pathogenesis.
Purpose of the Study:
- To investigate the association between MMD and the subsequent risk of developing PD.
- To explore the role of the RNF213 gene in the potential link between MMD and PD.
- To elucidate the molecular mechanisms involving alpha-synuclein and RNF213 in PD.
Main Methods:
- Retrospective cohort study using the Korean National Health Insurance Service database.
- Cox proportional hazards regression analysis to assess PD risk in MMD patients.
- In vitro experiments overexpressing SNCA and RNF213 in SH-SY5Y cells.
- Immunohistochemical analysis of postmortem brain tissues from PD patients and controls.
Main Results:
- MMD patients exhibited a significantly increased risk of developing PD (hazard ratio = 4.45).
- Overexpression of RNF213, particularly the Arg4810Lys variant, led to cytoplasmic inclusions, exacerbated by SNCA co-expression.
- Alpha-synuclein aggregates and RNF213 proteins were found to co-localize in PD brain tissues.
Conclusions:
- Patients with MMD have a substantially elevated risk of developing Parkinson's disease.
- A pathophysiological link between MMD and PD may exist, mediated by interactions between alpha-synuclein and RNF213.
- The RNF213 gene variant Arg4810Lys may play a role in the development of PD in MMD patients.
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