时间标签：数据日期 2026-11-05 · 生成时间 2026-11-05 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/11/02 – 2026/11/06 ｜ 情报发生日期 2026-11-05
研究问题
Whether rare but more severe LOF TMEM175 variants exert greater risk, or even act as causative monogenic factors in PD pathogenesis, remains unclear.In this study, we identified a rare LOF TMEM175 p.L275R mutation in a patient with early onset PD from a local cohort comprising approximately 800 cases, all of whom were enrolled at the Second Affiliated Hospital, Zhejiang University School of Medicine (SAHZU).
方法
Whereas TMEM175 deficiency accelerates α-synuclein aggregation in cultured neurons and mouse brains (11), GWASs have revealed a significant association of TMEM175 p.M393T with PD risk in European cohorts (15, 16), but not in some cohorts of other ancestries (7).；M393T, a common variant present in up to 20% of healthy individuals and patients with PD, is a relatively mild loss-of-function (LOF) trafficking mutation (11, 15).；Whether rare but more severe LOF TMEM175 variants exert greater risk, or even act as causative monogenic factors in PD pathogenesis, remains unclear.In this study, we identified a rare LOF TMEM175 p.L275R mutation in a patient with early onset PD from a local cohort comprising approximately 800 cases, all of whom were enrolled at the Second Affiliated Hospital, Zhejiang University School of Medicine (SAHZU).
核心结论
Recent genome-wide association studies (GWASs) suggest that as many as half of the known PD risk factors, such as GBA and CTSB variants, are autophagic or lysosomal genes (6, 7), suggesting that lysosome dysfunction is likely an elementary pathological mechanism in synucleinopathy and PD (8).The maintenance of an optimal lysosomal pH (4.5–5.0) is essential for lysosome function, not only for hydrolase-mediated degradation, but also for lysosomal membrane trafficking, cargo delivery, and catabolite export (9, 10).；Using patient-derived fibroblasts and induced pluripotent stem cells (iPSCs) and dopaminergic (iDA) neurons, we found that monoallelic expression of the mutant variant (+/L275R) was sufficient to cause profound defects in lysosomal acidification and degradation, leading to excessive neuronal aggregation of pathogenic α-synuclein.；However, we found that extracellular/luminal K+ (1–10 mM) did not significantly inhibit whole-cell and whole-LEL TMEM175-mediated H+ currents (Supplemental Figure 4, A, D, and G–I).
局限
However, 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB) and arachidonic acid, chemical agonists of TMEM175 (11), failed to further stimulate H+ currents through TMEM175L275R at pHE/L 4.6 or 3.0 (Figure 1, D and E, Supplemental Figure 2, G and H).；However, we found that extracellular/luminal K+ (1–10 mM) did not significantly inhibit whole-cell and whole-LEL TMEM175-mediated H+ currents (Supplemental Figure 4, A, D, and G–I).；However, DCPIB failed to further stimulate IK/Cs in TMEM175L275R-transfected cells, in sharp contrast to the dramatic (up to 100-fold) activation seen with TMEM175WT (Figure 1, F and G).
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全文来源
PubMed PMC JATS（正文 50,485 字符，题名指纹 0.77，已过 PubMed PMCID 官方关联 + 题名指纹 + 正文长度归属校验）
原文题录
- 中文题名：罕见 TMEM175 突变经质子门控与溶酶体酸化破坏驱动帕金森病病理
- 英文标题：A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.
- 期刊与标识：The Journal of clinical investigation · PMID 42969231 · DOI 10.1172/JCI206733 · PMC PMC13722388