Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice.

TitlePathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice.
Publication TypeJournal Article
Year of Publication2005
AuthorsGu X, Li C, Wei W, Lo V, Gong S, Li S-H, Iwasato T, Itohara S, Li X-J, Mody I, Heintz N, X Yang W
JournalNeuron
Volume46
Issue3
Pagination433-44
Date Published2005 May 05
ISSN0896-6273
KeywordsAnimals, Blotting, Western, Cell Communication, Cerebral Cortex, Disease Models, Animal, Huntington Disease, Immunohistochemistry, Mice, Mice, Mutant Strains, Microscopy, Electron, Transmission, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins
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.

DOI10.1016/j.neuron.2005.03.025
Alternate JournalNeuron
PubMed ID15882643
Grant ListAG19206 / AG / NIA NIH HHS / United States
NS04739 / NS / NINDS NIH HHS / United States
NS049501 / NS / NINDS NIH HHS / United States
NS41669 / NS / NINDS NIH HHS / United States