Human Molecular Genetics Advance Access originally published online on August 27, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2609-2623
DOI: 10.1093/hmg/ddg293
© 2003 Oxford University Press
Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy
1Center for Research in Neuroscience, McGill University, and the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada and 2Centre de recherché du CHUM, Hopital Notre-Dame, Universite de Montreal, 1560 Sherbrook East, Montreal, Quebec H2L 4M1, Canada
Received May 23, 2003; Revised August 5, 2003; Accepted August 16, 2003
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy that results from small expansions of a polyalanine tract in the PABPN1 gene. Intranuclear inclusions are the pathological hallmark of OPMD. The mechanism by which protein aggregation in OPMD might relate to a toxic gain-of-function has so far remained elusive. Whether protein aggregates themselves are pathogenic or are the consequence of an unidentified underlying molecular mechanism is still unclear. Here, we report that protein aggregation in a cell model of OPMD directly impaires the function of the ubiquitin–proteasome pathway (UPP) as well as molecular chaperone functions. The proteasome inhibitor lactacystin causes significant increase of protein aggregation and toxicity. Moreover, overexpression of molecular chaperones (HSP40 and HSP70) suppressed protein aggregation and toxicity. We also provide evidence that mPABPN1–ala17 protein aggregation proportionally correlates with toxicity. Furthermore, we show that co-expression of chaperones in our OPMD cell model increases the solubility of mPABPN1-ala17 and transfected cell survival rate. Our studies suggest that molecular regulators of polyalanine protein solubility and degradation may provide insights into new mechanisms in OPMD pathogenesis. Further analysis of the cellular and molecular mechanisms by which UPP and molecular chaperones influence the degradation of misfolded proteins could provide novel concepts and targets for the treatment and understanding of the pathogenesis of OPMD and neurodegenerative diseases.
* To whom correspondence should be addressed at: Room L7-224, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. Tel: +1 5149348094; Fax: +1 5149348265; Email: guy.rouleau{at}mcgill.ca
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