Calcium leak through ryanodine receptor is involved in neuronal death induced by mutant huntingtin

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Huntington's disease (HD) is a neurodegenerative disorder linked to expanded polyglutamine (polyQ) in huntingtin (htt).
• Altered calcium (Ca(2+)) homeostasis is implicated in HD pathogenesis, but underlying mechanisms are unclear.
• Ryanodine receptors (RyRs) are endoplasmic reticulum Ca(2+) channels potentially involved in HD.

Purpose of the Study:

• To investigate the role of ryanodine receptor (RyR) in mutant huntingtin (htt)-induced neuronal death.
• To elucidate the molecular mechanisms linking altered Ca(2+) homeostasis to HD pathogenesis.

Main Methods:

• Utilized cell-based assays with mutant htt expression.
• Employed intracellular Ca(2+) imaging to monitor Ca(2+) dynamics.
• Tested the effects of RyR inhibitors and FK506-binding protein 12 (FKBP12) on cell survival and Ca(2+) leak.
• Examined neurons from R6/2 HD model mice.

Main Results:

• Inhibiting RyR attenuated mutant htt-induced neuronal death.
• Co-expression of RyR exacerbated htt toxicity.
• Mutant htt caused excessive basal Ca(2+) release (leak) via RyR, depleting intracellular Ca(2+) stores.
• Ca(2+) leak through RyR was observed in neurons from HD model mice.
• FKBP12, a RyR stabilizer, reduced Ca(2+) leak and neuronal cell death.

Conclusions:

• Altered ryanodine receptor (RyR) function is implicated in mutant huntingtin-induced neuronal cell death.
• RyR-mediated Ca(2+) leak contributes to the pathogenesis of Huntington's disease.
• Stabilizing RyR function with agents like FKBP12 may offer a therapeutic benefit for HD.