title: Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice.
abstract: Expanded polyglutamine (polyQ) proteins in Huntington's disease (HD) as well as other polyQ disorders are known to elicit a variety of intracellular toxicities, but it remains unclear whether polyQ proteins can elicit pathological cell-cell interactions which are critical to disease pathogenesis. To test this possibility, we have created conditional HD mice expressing a neuropathogenic form of mutant huntingtin (mhtt-exon1) in discrete neuronal populations. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, including cortical interneurons, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides genetic evidence that pathological cell-cell interactions elicited by neuropathogenic forms of mhtt can critically contribute to cortical pathogenesis in a HD mouse model.
authors.affiliation: Center for Neurobehavioral Genetics, Neuropsychiatric Institute, Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Gu
authors.forename: Chenjian
authors.initials: C
authors.lastname: Li
authors.forename: Weizheng
authors.initials: W
authors.lastname: Wei
authors.forename: Victor
authors.initials: V
authors.lastname: Lo
authors.forename: Shiaoching
authors.initials: S
authors.lastname: Gong
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwasato
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Istvan
authors.initials: I
authors.lastname: Mody
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Heintz
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins