Role of inositol 1,4,5-trishosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias

  • Bezprozvanny I
  • 50


    Mendeley users who have this article in their library.
  • 50


    Citations of this article.


Huntington's disease (HD) and spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative disorders. HD is caused by polyglutamine (polyQ) expansion in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium spiny striatal neurons (MSN). Many SCAs are caused by polyQ-expansion in ataxin proteins and primarily affect cerebellar Purkinje cells. The reasons for neuronal dysfunction and death in HD and SCAs remain poorly understood and no cure is available for the patients. Our laboratory discovered that mutant huntingtin, ataxin-2 and ataxin-3 proteins specifically bind to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1), an intracellular Ca(2+) release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP(3)R1 causes sensitization of IP(3)R1 to activation by IP(3) in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca(2+) signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection between abnormal Ca(2+) signaling and neuronal cell death in experiments with HD, SCA2 and SCA3 transgenic mouse models. Additional data in the literature indicate that abnormal neuronal Ca(2+) signaling may also play an important role in pathogenesis of SCAl, SCA5, SCA6, SCA14 and SCA15/16. Based on these results I propose that IP(3)R and other Ca(2+) signaling proteins should be considered as potential therapeutic targets for treatment of HD and SCAs.

Author-supplied keywords

  • Apoptosis
  • Ataxin-2
  • Ataxin-3
  • Calcium signaling
  • Huntingtin
  • Inositol 1,4,5-trisphosphate
  • Memantine
  • Mitochondria
  • NMDA receptor
  • Neurodegeneration
  • Polyglutamine expansion
  • Spinocerebellar ataxias
  • Transgenic mice

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document


  • Ilya Bezprozvanny

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free