Autophagy and polyglutamine diseases |
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Authors: | Jimenez-Sanchez Maria Thomson Frances Zavodszky Eszter Rubinsztein David C |
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Affiliation: | Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. |
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Abstract: | In polyglutamine diseases, an abnormally elongated polyglutamine tract results in protein misfolding and accumulation of intracellular aggregates. The length of the polyglutamine expansion correlates with the tendency of the mutant protein to aggregate, as well as with neuronal toxicity and earlier disease onset. Although currently there is no effective cure to prevent or slow down the progression of these neurodegenerative disorders, increasing the clearance of mutant proteins has been proposed as a potential therapeutic approach. The ubiquitin-proteasome system and autophagy are the two main degradative pathways responsible for eliminating misfolded and unnecessary proteins in the cell. We will review some of the studies that have proposed autophagy as a strategy to reduce the accumulation of polyglutamine-expanded protein aggregates and protect against mutant protein neurotoxicity. We will also discuss some of the currently known mechanisms that induce autophagy, which may be beneficial for the treatment of these and other neurodegenerative disorders. |
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Keywords: | HD, Huntington's disease SCA, spinocerebellar ataxia DRPLA, Denatorubral-pallidoluysian atrophy SBMA, spinal and bulbar muscular atropy Htt, Huntingtin UPS, ubiquitin–proteasome system HDL-2, Huntington's disease-like 2 IBs, inclusion bodies RNAi, RNA interference Atg, autophagy-related genes ER, endoplasmic reticulum PI3K, phosphatidylinositol 3-kinase JNK1, c-Jun N-terminal protein kinase 1 PE, phosphatidylethanolamine SNAREs, soluble N-ethylmaleimide-sensitive factor attachment protein receptors mTOR, mammalian target of rapamycin PI-3-P, phosphatidylinositol-3-phosphate ROS, reactive oxygen species IP3, inositol-1,4,5-triphosphate IP3R, IP3 receptors cAMP, cyclic AMP IMPase, inositol monophosphatase GSK3β, glycogen synthase kinase-3 β I1R, imidazoline-1-receptor SMERs, small molecule enhancers of rapamycin SMIRs, small molecule inhibitors of rapamycin |
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