Human Molecular Genetics Advance Access published online on December 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi460
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1 Departments of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK; Department of Genetics, University of Cambridge, CB2 3EH, UK
* To whom correspondence should be addressed. Many aggregate-prone proteins, including proteins with long polyglutamine or polyalanine tracts, cause human diseases. Polyalanine proteins may also be present in 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.
Received November 2, 2005
Revised December 2, 2005
Accepted December 14, 2005
Article
Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion
Zdenek Berger 1,
Janet E. Davies 2,
Shouqing Luo 2,
Matthieu Y. Pasco 3,
Irina Majoul 4,
Cahir J. O'Kane 3,
and
David C. Rubinsztein 2 *
2 Departments of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK
3 Department of Genetics, University of Cambridge, CB2 3EH, UK
4 Departments of Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK
David C. Rubinsztein, E-mail: dcr1000{at}cus.cam.ac.uk
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