Human Molecular Genetics Advance Access originally published online on December 21, 2005
Human Molecular Genetics 2006 15(3):453-465; doi:10.1093/hmg/ddi460
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Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion
1Department of Medical Genetics and 2Department of Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK and 3Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK
* To whom correspondence should be addressed. Tel: +44 1223762608; Fax: +44 1223331206; Email: dcr1000{at}cus.cam.ac.uk
Received November 2, 2005; Revised December 2, 2005; Accepted December 14, 2005
Many aggregate-prone proteins, including proteins with long polyglutamine or polyalanine tracts, cause human diseases. Polyalanine proteins may also be present in the tissue of polyglutamine diseases as a result of frameshifting of the primary polyglutamine-encoding (CAG)n repeat mutation. We have generated a Drosophila model expressing green fluorescent protein tagged to 37 alanines that manifests both toxicity and inclusion formation in various tissues. Surprisingly, we show that this aggregate-prone protein with a polyalanine expansion can also protect against polyglutamine toxicity, which can be explained by induction of heat-shock response. A heat-shock response was also seen in an oculopharyngeal muscular dystrophy mouse model expressing an authentic polyalanine-expanded protein. We also show that long polyalanines can protect against a pro-apoptotic stimulus or the toxicity caused by the long polyalanines themselves. Thus, overexpression of an aggregate-prone protein without any normal functions can result in both pathogenic and protective effects in cell culture and in vivo.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
The last two authors are joint Senior Authors.
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