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, David C. Rubinsztein*

*Corresponding author for this work
28 Citations (Scopus)


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.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number3
Pages (from-to)453-465
Number of pages13
Publication statusPublished - 01.02.2006

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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