Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease

Hua Zhang, Qin Li, Rona K. Graham, Elizabeth Slow, Michael R. Hayden, Ilya Bezprozvanny

Research output: Contribution to journalArticle

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Abstract

Huntington's disease (HD) is caused by a progressive loss of striatal medium spiny neurons (MSN). The molecular trigger of HD is a polyglutamine expansion in the Huntingtin protein (Htt). The mutant Htt protein forms insoluble nuclear aggregates which have been proposed to play a key role in causing neuronal cell death in HD. Other lines of investigation suggest that expression of mutant Htt facilitates activity of the NR2B subtype of NMDA receptors and the type 1 inositol 1,4,5-trisphosphate receptors (InsP3R1), and that disturbed calcium (Ca2+) signaling causes apoptosis of MSNs in HD. The YAC128 transgenic HD mouse model expresses the full-length human Htt protein with 120Q CAG repeat expansion and displays an age-dependent loss of striatal neurons as seen in human HD brain. In contrast, the shortstop mice express an amino-terminal fragment of the mutant Htt protein (exons 1 and 2) and display no behavioral abnormalities or striatal neurodegeneration despite widespread formation of neuronal inclusions. Here we compared Ca2+ signals in primary MSN neuronal cultures derived from YAC128 and shortstop mice to their wild-type non-transgenic littermates. Repetitive application of glutamate results in supranormal Ca2+ responses in YAC128 MSNs, but not in shortstop MSNs. In addition, while currents mediated by the NR2B subtype of NMDA receptors were increased in YAC128 MSNs, currents in SS MSNs were found to be similar to WT. Furthermore, YAC128 MSNs were sensitized to glutamate-induced apoptosis. Consistent with these findings, we found that application of glutamate induced rapid loss of mitochondrial membrane potential in YAC128 MSNs. In contrast, SS MSNs do not show increased cell death postglutamate treatment nor accelerated loss of mitochondrial membrane potential following glutamate stimulation. Glutamate-induced loss of mitochondrial membrane potential in YAC128 MSNs could be prevented by inhibitors of NR2B NMDA receptors and mGluR1/5 receptors. Our results are consistent with the hypothesis that disturbed neuronal Ca2+ signaling plays a significant role in the degeneration of MSN containing full-length mutant Httexp. Furthermore, the results obtained with neurons from shortstop mice provide additional evidence that not all fragments of mutant Httexp are toxic to neurons.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalNeurobiology of Disease
Volume31
Issue number1
DOIs
StatePublished - Jul 2008

Fingerprint

Corpus Striatum
Huntington Disease
Glutamic Acid
Apoptosis
Neurons
Mitochondrial Membrane Potential
Mutant Proteins
Cell Death
Inositol 1,4,5-Trisphosphate Receptors
Proteins
Calcium Signaling
Poisons
Exons
Huntingtin Protein
Brain
NR2B NMDA receptor

Keywords

  • Apoptosis
  • Calcium
  • Excitotoxicity
  • Huntington's disease
  • Mitochondria
  • NMDAR
  • Transgenic mouse

ASJC Scopus subject areas

  • Neurology

Cite this

Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease. / Zhang, Hua; Li, Qin; Graham, Rona K.; Slow, Elizabeth; Hayden, Michael R.; Bezprozvanny, Ilya.

In: Neurobiology of Disease, Vol. 31, No. 1, 07.2008, p. 80-88.

Research output: Contribution to journalArticle

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