Macroautophagy upregulation - a candidate therapeutic strategy to enhance clearance of toxic intracellular aggregate-prone proteins
David C. Rubinsztein
Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2XY, UK
The deposition of protein aggregates in specific target organs is a
feature of many human diseases referred to as Protein Conformation
Disorders (PCD). These include Alzheimer's disease, Parkinson's
disease, Huntington's disease (HD) and Oculopharyngeal muscular
dystrophy (OPMD). The role of aggregates in these diseases has been a
subject of vigorous debate. However, irrespective of the nature(s) of
the toxic species, it is desirable for cells to be able to control the
levels of these toxic proteins and restrict their accumulation.
Macroautophagy (which I will call autophagy) is involved in the
clearance of mutant huntingtin in cell models, in flies and in mouse
models of disease. Mutations that impede autophagy enhance the toxicity
of this mutant protein. Activation of autophagy with rapamycin prior to
disease onset reduces the levels of the mutant protein, resulting in
decreased aggregate formation and attenuated toxicity/delayed onset.
Our data suggest that these protective effects are not confined to
mutant huntingtin but may be relevant to certain other PCDs in vivo.
Key words:
Huntington's disease; macroautophagy; autophagy; polyglutamine
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