Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Jennifer Bradford, Ji Yeon Shin, Meredith Roberts, Chuan En Wang, Xiao Jiang Li, Shihua Li

Research output: Contribution to journalArticle

196 Citations (Scopus)

Abstract

Huntington disease (HD) is an inherited neurological disorder caused by a polyglutamine expansion in the protein huntingtin and is characterized by selective neurodegeneration that preferentially occurs in striatal medium spiny neurons. Because the medium spiny neurons are innervated abundantly by glutamatergic axons from cortical neurons, the preferential degeneration in the striatal neurons supports the glutamate excitotoxicity theory for HD pathogenesis. Thus, glutamate uptake by glia may be particularly important for preventing glutamate excitotoxicity in HD. Although mutant huntingtin is expressed ubiquitously in various types of cells, it accumulates and forms aggregates in fewer glial cells than in neuronal cells. It remains largely unknown whether and how mutant huntingtin in glia can contribute to the neurological symptoms of HD. We generated transgenic mice that express N-terminal mutant huntingtin in astrocytes, a major type of glial cell that remove extracellular glutamate in the brain. Although transgenic mutant huntingtin in astrocytes is expressed below the endogenous level, it can cause age-dependent neurological phenotypes in transgenic mice. Mice expressing mutant huntingtin show body weight loss, have motor function deficits, and die earlier than wild-type or control transgenic mice. We also found that mutant huntingtin in astrocytes decreases the expression of glutamate transporter by increasing its binding to Sp1 and reducing the association of Sp1 with the promoter of glutamate transporter. These results imply an important role for glial mutant huntingtin in HD pathology and suggest possibilities for treatment.

Original languageEnglish (US)
Pages (from-to)22480-22485
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number52
DOIs
StatePublished - Dec 19 2009

Fingerprint

Huntington Disease
Neuroglia
Astrocytes
Glutamic Acid
Transgenic Mice
Brain
Amino Acid Transport System X-AG
Corpus Striatum
Neurons
Nerve Degeneration
Nervous System Diseases
Axons
Weight Loss
Body Weight
Pathology
Phenotype

Keywords

  • Excitotoxicity
  • Glia
  • Glutamate
  • Neurodegeneration
  • Polyglutamine

ASJC Scopus subject areas

  • General

Cite this

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. / Bradford, Jennifer; Shin, Ji Yeon; Roberts, Meredith; Wang, Chuan En; Li, Xiao Jiang; Li, Shihua.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 52, 19.12.2009, p. 22480-22485.

Research output: Contribution to journalArticle

Bradford, Jennifer ; Shin, Ji Yeon ; Roberts, Meredith ; Wang, Chuan En ; Li, Xiao Jiang ; Li, Shihua. / Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 52. pp. 22480-22485.
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