Molecular pathogenesis of Huntington's disease: The role of excitotoxicity

Mahmoud A. Pouladi, Ilya Bezprozvanny, Lynn A. Raymond, Michael R. Hayden

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

Abstract

This chapter discusses the role of excitotoxicity in the molecular pathogenesis of Huntington's disease (HD). HD is a progressive neurological disorder characterized by involuntary movements, emotional disturbances, and dementia. The underlying genetic lesion is an expansion of a CAG trinucleotide repeat in the HD gene that results in an expanded polyglutamine (polyQ) stretch at the N-terminus of the huntingtin protein (htt). The cardinal neuropathological feature of HD is a selective loss in the striatum of medium-sized spiny neurons. Recent evidence strongly implicates aberrant glutamate signaling, disrupted neuronal calcium handling, and the accompanying excitotoxicity in the pathogenesis of HD. The involvement of excitotoxicity in the pathogenesis of HD was first suggested by rodent studies in which intrastriatal injections of kainic acid (KA) or quinolinic acid (QA, an NMDA receptor agonist) produced lesions that mimicked many of the neurochemical and histopathological features of HD, and was associated with HD-like behavioral deficits. A number of human and animal studies have since identified defects in NMDA and mGluR5 signaling, as well as mitochondrial calcium handling in HD patients and animal models of HD. Together, these studies give rise to a coherent, multifactorial model of mutant huntingtin-mediated alteration of glutamate receptor activity, and calcium signaling as a primary contributor to neuronal degeneration in HD.

Original languageEnglish (US)
Title of host publicationGenetic Instabilities and Neurological Diseases, Second Edition
PublisherElsevier Inc.
Pages251-260
Number of pages10
ISBN (Print)9780123694621
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Pouladi, M. A., Bezprozvanny, I., Raymond, L. A., & Hayden, M. R. (2006). Molecular pathogenesis of Huntington's disease: The role of excitotoxicity. In Genetic Instabilities and Neurological Diseases, Second Edition (pp. 251-260). Elsevier Inc.. https://doi.org/10.1016/B978-012369462-1/50016-8