summary
The accumulation of mutant aggregate-prone proteins is a feature of several human disorders, collectively referred to as protein conformation disorders or proteinopathies. We have shown that autophagy, a cytosolic, non-specific bulk degradation system, is an important clearance route for many cytosolic toxic, aggregate-prone proteins, like mutant huntingtin and mutant \({\bf \alpha}\)-synucleins. Induction of autophagy enhances the clearance of both soluble and aggregated forms of the mutant protein, and protects against toxicity caused by these mutations in cell, fly, and mouse models. Inhibition of autophagy has opposite effects. Thus, the autophagic pathway may represent a possible therapeutic target in the treatment of certain protein conformation disorders.
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References
Ross, C. A. and Poirier, M. A. (2004) Protein aggregation and neurodegenerative disease. Nat. Med. 10(Suppl), S10–17.
Narain, Y., Wyttenbach, A., Rankin, J., Furlong, R. A. and Rubinsztein, D. C. (1999) A molecular investigation of true dominance in Huntington’s disease. J. Med. Genet. 36, 739–746.
Klionsky, D. J. and Ohsumi, Y. (1999) Vacuolar import of proteins and organelles from the cytoplasm. Annu. Rev. Cell Dev. Biol., 15, 1–32.
Schmelzle, T. and Hall, M. N. (2000) TOR, a central controller of cell growth. Cell 103, 253–262.
Kovacs, A. L., Gordon, P. B., Grotterod, E. M. and Seglen, P. O. (1998) Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP. Biol. Chem. 379, 1341–1347.
Yamamoto, A., Tagawa, Y., Yoshimori, T., Moriyama, Y., Masaki, R. and Tashiro, Y. (1998) Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 23, 33–42.
Hara, T., Nakamura, K., Matsui, M., et al. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889.
Komatsu, M., Waguri, S., Chiba, T., et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884.
Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117.
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. and Rubinsztein, D. C. (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol. Chem. 278, 25009–25013.
Ravikumar, B., Vacher, C., Berger, Z., et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595.
Sarkar, S., Floto, R.A., Berger, Z., et al. (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111.
Wyttenbach, A., Swartz, J., Kita, H., et al. (2001) Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington’s disease. Hum. Mol. Genet. 10, 1829–1845.
Kabeya, Y., Mizushima, N., Ueno, T., et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728.
Wyttenbach, A., Sauvageot, O., Carmichael, J., Diaz-Latoud, C., Arrigo, A. P. and Rubinsztein, D.C. (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum. Mol. Genet. 11, 1137–1151.
Acknowledgments
We thank T. Yoshimori (National Institute of Genetics, Japan) for EGFP-LC3 construct. We are grateful to the Wellcome Trust (Senior Clinical Fellowship to DCR), MRC, EU (EUROSCA) and Muscular Dystrophy Campaign for funding.
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© 2008 Humana Press, a part of Springer Science+Business Media, LLC
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Ravikumar, B., Sarkar, S., Rubinsztein, D.C. (2008). Clearance of Mutant Aggregate-Prone Proteins by Autophagy. In: Deretic, V. (eds) Autophagosome and Phagosome. Methods in Molecular Biology™, vol 445. Humana Press. https://doi.org/10.1007/978-1-59745-157-4_13
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DOI: https://doi.org/10.1007/978-1-59745-157-4_13
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