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

Jun Wu, Daniel Ryskamp, Lutz Birnbaumer, Ilya Bezprozvanny

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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 (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. 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.

Original languageEnglish (US)
Pages (from-to)35-50
Number of pages16
JournalJournal of Huntington's disease
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • beamwalk
  • Huntingtin
  • imaging
  • STIM1
  • store-operated calcium entry
  • synaptic
  • TRPC1

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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