Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease
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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STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death
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