Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment

Chem Biol. 2011 Jun 24;18(6):777-93. doi: 10.1016/j.chembiol.2011.04.012.

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate-toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism*
  • Cells, Cultured
  • Disease Models, Animal
  • Drosophila
  • Fura-2 / chemistry
  • Glutamic Acid / pharmacology
  • Huntingtin Protein
  • Huntington Disease / drug therapy
  • Huntington Disease / metabolism*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Neurons / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phenyl Ethers / chemistry*
  • Phenyl Ethers / pharmacology
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • TRPC Cation Channels / antagonists & inhibitors
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism

Substances

  • EVP 4593
  • Htt protein, mouse
  • Huntingtin Protein
  • NF-kappa B
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Phenyl Ethers
  • Quinazolines
  • RNA, Small Interfering
  • TRPC Cation Channels
  • transient receptor potential cation channel, subfamily C, member 1
  • Glutamic Acid
  • Calcium
  • Fura-2