Aggregate‐Prone Proteins Are Cleared from the Cytosol by Autophagy: Therapeutic Implications
Section snippets
Proteinopathies
Intracellular protein misfolding and aggregation are features of many late‐onset neurodegenerative diseases, called proteinopathies. These include Alzheimer's disease, Parkinson's disease, tauopathies, and various diseases caused by abnormally expanded tracts of the amino acid glutamine, like Huntington's disease (HD). HD is an autosomal‐dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion, which results in an abnormally long polyglutamine (polyQ) tract in the
Intracytoplasmic Aggregate‐Prone Proteins Are Cleared by Autophagy
Our initial studies used either an exon 1 fragment of huntingtin with 74 glutamines or 19 alanine repeats fused to GFP as model aggregate‐prone proteins and demonstrated that they can be cleared by both the proteasome and autophagy in cell culture (Ravikumar et al., 2002). Autophagy may be the preferential route of clearance of these proteins as the proteasome is unable to cleave within the polyglutamine tract (Holmberg 2004, Venkatraman 2004) and the narrow proteasome barrel cannot admit and
Autophagy Induction Has Additional Antiapoptotic Consequences
In addition to the protective effect of rapamycin via enhanced clearance of aggregate‐prone proteins, our studies suggest that rapamycin can have other cytoprotective effects by protecting cells and Drosophila against subsequent diverse apoptotic insults (Ravikumar et al., 2006). This protective effect is, however, lost when autophagy is inhibited. There are two major apoptotic cascades in a cell, namely the intrinsic and extrinsic pathways. The intrinsic pathway requires
A New mTOR‐Independent Autophagy Pathway
While rapamycin is the most specific kinase inhibitor known, its target, mTOR, controls many processes independent of autophagy (Wullschleger et al., 2006) and the way that mTOR regulates autophagy is still unclear. This results in side effects with long‐term rapamycin therapy, including poor wound healing and some immunosuppression, although we are not aware of side effects that have been attributed to enhanced autophagy in people taking rapamycin. Thus, the identification of more specific
A Protective Role for Aggregates: Autophagy Upregulation
Increased numbers of autophagosome‐like structures have also been reported in the brains of HD patients (Sapp et al., 1997). We confirmed in cell models of HD that there is an increase in the numbers of autophagosomes—however, this appeared to be a feature specifically of the cells with visible aggregates. We observed the same phenomenon with other mutant polyglutamine proteins like mutant ataxin‐1 (responsible for SCA type‐I). Our studies suggest that the increased autophagic activity in these
Conclusions
Our data suggest that aggregate‐prone intracytosolic proteins are autophagy substrates and that their clearance can be enhanced by upregulating this clearance pathway. In fly and mouse models of HD, autophagy upregulation is associated with beneficial effects. Ideally, we would like to initiate such treatment strategies in HD patients as early as possible with the aim of delaying onset of disease. If one can delay the symptoms of a disease that has a median onset of 40 years until after 90
Acknowledgments
The work in our laboratory has been funded by a Wellcome Trust Senior Fellowship in Clinical Science, an MRC Program Grant, Wyeth and EU Framework VI (EUROSCA).
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