Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease

Journal of Huntington's Disease
Jun WuIlya Bezprozvanny

Abstract

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 (InsP3R1) to InsP3. 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. We sought to identify calcium channels supporting supranormal nSOC in HD MSNs and to validate these channels as potential therapeutic targets for HD. 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. 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 activat...Continue Reading

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Citations

May 12, 2019·International Journal of Molecular Sciences·Karolina Serwach, Joanna Gruszczynska-Biegala
Dec 1, 2019·Journal of Medical Entomology·Konan F AssouhoAhoua Yapi
Jan 24, 2019·International Journal of Molecular Sciences·Paloma González-SánchezAraceli Del Arco
Oct 15, 2019·Frontiers in Neuroscience·Daniel A RyskampIlya Bezprozvanny
Jun 6, 2020·Antioxidants & Redox Signaling·Lígia Fão, Ana Cristina Rego
Apr 8, 2020·Frontiers in Aging Neuroscience·Lu LiuShengmei Zhu
Sep 26, 2019·Frontiers in Neuroscience·Daniel A RyskampIlya Bezprozvanny
Apr 20, 2019·Frontiers in Molecular Biosciences·Talya ShachamGerardo Z Lederkremer
Sep 3, 2020·Cells·Xingjuan ChenAlexander G Obukhov
Dec 18, 2020·Frontiers in Cellular Neuroscience·Isis Zhang, Huijuan Hu
Jan 12, 2021·Frontiers in Cell and Developmental Biology·Magdalena Czeredys
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Jaepyo JeonMichael X Zhu
Feb 20, 2021·Frontiers in Cell and Developmental Biology·Vladimir A VigontElena V Kaznacheyeva
Aug 29, 2021·Life Sciences·Ritika LuthraKriti Bhandari

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Methods Mentioned

BETA
X-ray
transgenic
genotyping
PCR
electrophoresis
co-immunoprecipitation
coimmunoprecipitation
dissection
reverse transcription PCR
immunoprecipitation

Software Mentioned

NeuronStudio
ImageJ

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