Aggregate‐Prone Proteins Are Cleared from the Cytosol by Autophagy: Therapeutic Implications

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Intracellular protein misfolding/aggregation are features of many late‐onset neurodegenerative diseases, called proteinopathies. These include Alzheimer's disease, Parkinson's disease, tauopathies, and polyglutamine expansion diseases [e.g., Huntington's disease; and various spinocerebellar ataxias (SCAs), like SCA3]. There are no effective strategies to slow or prevent the neurodegeneration resulting from these diseases in humans. The mutations causing many proteinopathies (e.g., polyglutamine diseases and tauopathies) confer novel toxic functions on the specific protein, and disease severity frequently correlates with the expression levels of the protein. Thus, the factors regulating the synthesis and clearance of these aggregate‐prone proteins are putative therapeutic targets. The proteasome and autophagy‐lysosomal pathways are the major routes for mutant huntingtin fragment clearance. While the narrow proteasome barrel precludes entry of oligomers/aggregates of mutant huntingtin (or other aggregate‐prone intracellular proteins), such substrates can be degraded by macroautophagy (which we will call autophagy). We showed that the autophagy inducer rapamycin reduced the levels of soluble and aggregated huntingtin and attenuated its toxicity in cells, and in transgenic Drosophila and mouse models. We extended the range of intracellular proteinopathy substrates that are cleared by autophagy to a wide range of other targets, including proteins mutated in certain SCAs, forms of α‐synuclein mutated in familial forms of Parkinson's disease, and tau mutants that cause frontotemporal dementia/tauopathy. In this chapter, we consider the therapeutic potential of autophagy upregulation for various proteinopathies, and describe how this strategy may act both by removing the primary toxin (the misfolded/aggregate‐prone protein) and by reducing susceptibility to apoptotic insults.

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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