Journal Article

Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion

Zdenek Berger, Janet E. Davies, Shouqing Luo, Matthieu Y. Pasco, Irina Majoul, Cahir J. O'Kane and David C. Rubinsztein

in Human Molecular Genetics

Volume 15, issue 3, pages 453-465
Published in print February 2006 | ISSN: 0964-6906
Published online December 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi460
Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion

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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.

Journal Article.  10051 words.  Illustrated.

Subjects: Genetics and Genomics

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