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Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease.

TitleAccumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease.
Publication TypeJournal Article
Year of Publication2008
AuthorsWang C-E, Tydlacka S, Orr AL, Yang S-H, Graham RK, Hayden MR, Li S, Chan AWS, Li X-J
JournalHum Mol Genet
Volume17
Issue17
Pagination2738-51
Date Published2008 Sep 01
ISSN1460-2083
KeywordsAnimals, Animals, Genetically Modified, Brain, Haplorhini, Humans, Huntington Disease, Mice, Mice, Transgenic, Neurons, Serotonin Plasma Membrane Transport Proteins, Transcription, Genetic
Abstract

A number of mouse models expressing mutant huntingtin (htt) with an expanded polyglutamine (polyQ) domain are useful for studying the pathogenesis of Huntington's disease (HD) and identifying appropriate therapies. However, these models exhibit neurological phenotypes that differ in their severity and nature. Understanding how transgenic htt leads to variable neuropathology in animal models would shed light on the pathogenesis of HD and help us to choose HD models for investigation. By comparing the expression of mutant htt at the transcriptional and protein levels in transgenic mice expressing N-terminal or full-length mutant htt, we found that the accumulation and aggregation of mutant htt in the brain is determined by htt context. HD mouse models demonstrating more severe phenotypes show earlier accumulation of N-terminal mutant htt fragments, which leads to the formation of htt aggregates that are primarily present in neuronal nuclei and processes, as well as glial cells. Similarly, transgenic monkeys expressing exon-1 htt with a 147-glutamine repeat (147Q) died early and showed abundant neuropil aggregates in swelling neuronal processes. Fractionation of HD150Q knock-in mice brains revealed an age-dependent accumulation of N-terminal mutant htt fragments in the nucleus and synaptosomes, and this accumulation was most pronounced in the striatum due to decreased proteasomal activity. Our findings suggest that the neuropathological phenotypes of HD stem largely from the accumulation of N-terminal mutant htt fragments and that this accumulation is determined by htt context and cell-type-dependent clearance of mutant htt.

DOI10.1093/hmg/ddn175
Alternate JournalHum. Mol. Genet.
PubMed ID18558632
PubMed Central IDPMC2733806
Grant ListR01 NS041669 / NS / NINDS NIH HHS / United States
NS045016 / NS / NINDS NIH HHS / United States
NS041669 / NS / NINDS NIH HHS / United States
R01 AG019206 / AG / NIA NIH HHS / United States
AG019206 / AG / NIA NIH HHS / United States
R01 NS045016 / NS / NINDS NIH HHS / United States
R01 AG031153 / AG / NIA NIH HHS / United States
R24RR018827 / RR / NCRR NIH HHS / United States
R24 OD010930 / OD / NIH HHS / United States
R01 NS036232 / NS / NINDS NIH HHS / United States