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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R173-R186
DOI: 10.1093/hmg/ddg295
© 2003 Oxford University Press

Pathogenesis of polyglutamine disorders: aggregation revisited

Andrej Michalik and Christine Van Broeckhoven*

Department of Molecular Genetics, Neurogenetics Group, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium

Received June 25, 2003; Accepted August 14, 2003

Expansion of CAG trinucleotide repeats coding for polyglutamine in unrelated proteins causes at least nine late-onset progressive neurodegenerative disorders, including Huntington's disease and a number of spinocerebellar ataxias. Expanded polyglutamine provokes a dominant gain-of-function neurotoxicity, regardless of the specific protein context within which it resides. Nevertheless, the protein context does modulate polyglutamine toxicity, as evidenced by the distinct clinical and pathological features of the various disorders. Importantly, polyglutamine toxicity might derive from its ability to aggregate. Indeed, aggregation probably underlies some defining attributes of the polyglutamine disorders, such as their late onset, progressive nature, and the dependence of onset age on polyglutamine length. However, the central role of aggregation in polyglutamine pathogenesis has been challenged by several studies, which instead argued that the soluble form of the disease proteins is responsible for neuronal damage. Thus, the question whether polyglutamine aggregates are deleterious, harmless or protective remains the most passionately disputed issue in the study of these diseases. In this review, we attempt to reconcile some of these controversies.

* To whom correspondence should be addressed at: Department of Molecular Genetics VIB8, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium. Tel: +32 38202601; Fax: +32 38202541; Email: christine.vanbroeckhoven{at}ua.ac.be


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