Movement disorders : official journal of the Movement Disorder Society · 2026
Cell-Type-Specific Causal Inference Unveils Novel Targets for Parkinson's Disease.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Gu Si-Chun, Sun Qiao Yang, Zhang Wei, Shen Chang-Yi, Su Hang, Xie Fang, Yuan Can-Xing, Zhou Zhi-Dong, Tan Eng King, Ye Qing
Аннотация
BACKGROUND: Parkinson's disease (PD) involves heterogeneous neurodegenerative processes across brain cell types. The cell-type-specific effects of genetic risk remain unclear.
OBJECTIVE: We aimed to identify cell-type-specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities.
METHODS: We performed the first cell-stratified Mendelian randomization integrating single-cell expression quantitative trait loci data from eight brain cell types with large PD genome-wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses.
RESULTS: Thirteen significant causal associations for four genes (ARL17A, ARL17B, KANSL1, LRRC37A) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B, KANSL1, and LRRC37A were protective. Gene expression correlated with disease severity and showed cell-type-specific dysregulation. Drug-gene interaction screen highlighted US Food and Drug Administration-approved agents including raloxifene and dorzolamide as potential therapeutic modulators.
CONCLUSIONS: This study contributed to cell-type-specific genetic mechanisms in PD, linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.
OBJECTIVE: We aimed to identify cell-type-specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities.
METHODS: We performed the first cell-stratified Mendelian randomization integrating single-cell expression quantitative trait loci data from eight brain cell types with large PD genome-wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses.
RESULTS: Thirteen significant causal associations for four genes (ARL17A, ARL17B, KANSL1, LRRC37A) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B, KANSL1, and LRRC37A were protective. Gene expression correlated with disease severity and showed cell-type-specific dysregulation. Drug-gene interaction screen highlighted US Food and Drug Administration-approved agents including raloxifene and dorzolamide as potential therapeutic modulators.
CONCLUSIONS: This study contributed to cell-type-specific genetic mechanisms in PD, linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.