The roles of the ubiquitin-proteasome and autophagy-lysosome pathways in Huntington’s disease and related conditions

Brinda Ravikumar, Sovan Sarkar, Zdenek Berger, David C Rubinsztein

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Huntington's disease (HD) is one of nine known conditions caused by a CAG trinucleotide repeat expansion that is translated into a polyglutamine tract in the disease protein. Genetic and transgenic data suggest that the primary effect of these CAG/polyglutamine expansions is to confer a toxic gain-of-function on the mutant protein. The cellular pathology of all known polyglutamine diseases is characterised by the accumulation of the relevant mutant protein along with other proteins in aggregates (also known as inclusions) in neurons in the disease brain. Such aggregates are seen in neuronal nuclei and processes in HD. The role of aggregates in these diseases has been a subject of vigorous debate. However, irrespective of the nature(s) of the toxic species of huntingtin, it is desirable for cells to be able to control the levels of these toxic proteins and restrict their accumulation. In this paper we will review the ubiquitin-proteasome and autophagy–lysosome routes for protein degradation and how they may be involved in the clearance of aggregate-prone proteins, exemplified by mutant huntingtin exon 1. We will also consider the possibilities that these protein degradation pathways may be perturbed as a consequence of the mutations that form the aggregate-prone proteins.
Original languageEnglish
Pages (from-to)141-8
Number of pages8
JournalClinical Neuroscience Research
Volume3
Issue number3
DOIs
Publication statusPublished - Sept 2003

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