Disturbed Ca2+ signalling and apoptosis of medium spiny neurons in Huntington's disease

Tie Shan Tang, Elizabeth Slow, Vitalie Lupu, Irina G. Stavrovskaya, Mutsuyuki Sugimori, Rodolfo Llinás, Bruce S. Kristal, Michael R. Hayden, Ilya Bezprozvanny

Research output: Contribution to journalArticle

278 Scopus citations

Abstract

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca 2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-AP3 and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD.

Original languageEnglish (US)
Pages (from-to)2602-2607
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number7
DOIs
StatePublished - Feb 15 2005

Keywords

  • Enoxaparin
  • Lovenox
  • Mitochondria
  • Neurodegeneration
  • Transgenic mouse

ASJC Scopus subject areas

  • General

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