期刊
JOURNAL OF HUNTINGTONS DISEASE
卷 7, 期 1, 页码 35-50出版社
IOS PRESS
DOI: 10.3233/JHD-170266
关键词
Huntingtin; synaptic; store-operated calcium entry; TRPC1; STIM1; imaging; beamwalk
资金
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [R01NS074376, R01NS056224, F32NS093786]
- NIH Intramural Research Program [Z01-ES-101684]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS056224, F32NS093786] Funding Source: NIH RePORTER
Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) to InsP(3). This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice. Objective: We sought to identify calcium channels supporting supranormal nSOC inHDMSNs and to validate these channels as potential therapeutic targets for HD. Methods: Cortico-striatal cultures were established from wild type and YAC128 HD mice and the density of MSN spines was quantified. The expression of candidate nSOC components was suppressed by RNAi knockdown and by CRISPR/Cas9 knockout. TRPC1 knockout mice were crossed with YAC128 HD mice for evaluation of motor performance in a beamwalk assay. Results: RNAi-mediated knockdown of TRPC1, TRPC6, Orai1, or Orai2, but not other TRPC isoforms or Orai3, rescued the density of YAC128 MSN spines. Knockdown of stromal interaction molecule 1 (STIM1), an ER calcium sensor and nSOC activator, also rescued YAC128 MSN spines. Knockdown of the same targets suppressed supranormal nSOC in YAC128 MSN spines. These channel subunits co-immunoprecipitated with STIM1 and STIM2 in synaptosomal lysates from mouse striata. Crossing YAC128 mice with TRPC1 knockout mice improved motor performance and rescued MSN spines in vitro and in vivo, indicating that inhibition of TRPC1 may serve as a neuroprotective strategy for HD treatment. Conclusions: TRPC1 channels constitute a potential therapeutic target for treatment of HD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据