Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion.
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.
Berger
Zdenek
Z
Department of Medical Genetics, University of Cambridge, Cambridge, UK.
Davies
Janet E
JE
Luo
Shouqing
S
Pasco
Matthieu Y
MY
Majoul
Irina
I
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018869:Heat-Shock Response; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D019680:Trinucleotide Repeat Expansion / Q000235:genetics / Q000502:physiology*
D010455:Peptides; C019529:polyalanine; C097188:polyglutamine