title: Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease.
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 (InsP(3)R1), and that disturbed calcium (Ca(2+)) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) signaling plays a significant role in the degeneration of MSN containing full-length mutant Htt(exp). Furthermore, the results obtained with neurons from shortstop mice provide additional evidence that not all fragments of mutant Htt(exp) are toxic to neurons.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Slow
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid