Berger, Z., Davies, J.E., Luo, S., Pasco, M.Y., Majoul, I., O'Kane, C.J., Rubinsztein, D.C. (2006). Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion.  Hum. Mol. Genet. 15(3): 453--465.

FBrf0190826

Research paper

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.