[General Articles] Altered Protein Acetylation in Polyglutamine Diseases

Author(s): L. Bodai, J. Pallos, L. M. Thompson, J. L. Marsh

Journal Name: Current Medicinal Chemistry

Volume 10 , Issue 23 , 2003

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Polyglutamine diseases are hereditary neurodegenerative disorders caused by the expansion of a CAG repeat in the disease gene. A dominant gain of function is associated with these expanded alleles. The resulting elongated polyglutamine repeats are thought to cause structural changes in the affected proteins, leading to aberrant interactions such as those that allow formation of extra- and intranuclear aggregates. However, self-association is not the only interaction the polyglutamine domain is capable of mediating. Many cellular proteins can be sequestered into inclusions or bound by more soluble forms of the mutant proteins. One group of proteins that binds to and whose activity may be altered by polyglutamines is Histone Acetyltransferases (HATs). HATs are responsible for the acetylation of histones and several other important proteins and this modification results in altered function of the target protein. HATs regulate cellular processes at levels as different as modifying transcriptional competence of chromosomes, temporal regulation of promoter activity and protein activation / inactivation. Recent studies show that the altered balance between protein acetylation and deacetylation may be a key process contributing to expanded polyglutamine-induced pathogenesis. The restoration of this balance is possible by the genetic or pharmacological reduction of the opposing enzyme group, i.e. the Histone Deacetylases (HDACs). Recent progress in HDAC research has made the development of inhibitors of specific HDAC family proteins possible and these compounds could be effective candidates for treatment of these devastating diseases.

Keywords: polyglutamine diseases, polyq, huntington's disease, neurodegeneration, protein acetylation, hat, hdac, hdac inhibitors

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Article Details

Year: 2003
Published on: 01 March, 2012
Page: [2577 - 2587]
Pages: 11
DOI: 10.2174/0929867033456530
Price: $65

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