Human Molecular Genetics, 2002, Vol. 11, No. 9 1107-1117
© 2002 Oxford University Press
Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
1Department of Medical Genetics and 2Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK
Protein conformational disorders (PCDs), such as Alzheimer's disease, Huntington's disease (HD), Parkinson's disease and oculopharyngeal muscular dystrophy, are associated with proteins that misfold and aggregate. Here we have used exon 1 of the HD gene with expanded polyglutamine [poly(Q)] repeats and enhanced green fluorescent protein tagged to 19 alanines as models for aggregate-prone proteins, to investigate the pathways mediating their degradation. Autophagy is involved in the degradation of these model proteins, since they accumulated when cells were treated with different inhibitors acting at distinct stages of the autophagy–lysosome pathway, in two different cell lines. Furthermore, rapamycin, which stimulates autophagy, enhanced the clearance of our aggregate-prone proteins. Rapamycin also reduced the appearance of aggregates and the cell death associated with the poly(Q) and polyalanine [poly(A)] expansions. Since rapamycin is used clinically, this drug or related analogues may be suitable candidates for therapeutic investigation in HD and related diseases. We have also re-examined the role of the proteasome, since previous studies in poly(Q) diseases have used lactacystin as an inhibitor – recent studies have shown that lactacystin may also affect lysosomal function. Both lactacystin and the specific proteasomal inhibitor epoxomicin increased soluble protein levels of the poly(Q) constructs, suggesting that these are also cleared by the proteasome. However, while poly(Q) aggregation was enhanced by lactacystin in our inducible PC12 cell model, aggregation was reduced by epoxomicin, suggesting that some other protein(s) induced by epoxomicin may regulate poly(Q) aggregation.
* To whom correspondence should be addressed. Tel:+44 01223 762608; Fax:+44 01223 331206; Email: dcr1000{at}cus.cam.ac.uk
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