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Mol Neurobiol. 2015 Dec;52(3):1297-1314. doi: 10.1007/s12035-014-8932-1. Epub 2014 Oct 22.

Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?

Author information

1
Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France.
2
Laboratoire de Physiologie Cérébrale, Centre National de la Recherche Scientifique, Université Paris Descartes, 45 rue des Saints Pères, 75006, Paris, France. philippe.djian@parisdescartes.fr.

Abstract

Huntington disease is a dominantly inherited disease of the central nervous system. The mutational expansion of polyglutamine beyond a critical length produces a toxic gain of function in huntingtin and results in neuronal death. In the course of the disease, expanded huntingtin is proteolyzed, becomes abnormally folded, and accumulates in oligomers, fibrils, and microscopic inclusions. The aggregated forms of the expanded protein are structurally diverse. Structural heterogeneity may explain why polyglutamine-containing aggregates could paradoxically be either toxic or neuroprotective. When defined, the toxic structures could then specifically be targeted by prophylactic or therapeutic drugs aimed at inhibiting polyglutamine aggregation.

KEYWORDS:

Amyloid; Fibrils; Huntingtin; Inclusions; Oligomers; β-Sheets

PMID:
25336039
DOI:
10.1007/s12035-014-8932-1
[Indexed for MEDLINE]

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