TAILIEUCHUNG - Báo cáo khoa học: Huntington’s disease: degradation of mutant huntingtin by autophagy

Autophagy is a nonspecific bulk degradation pathway for long-lived cyto-plasmic proteins, protein complexes, or damaged organelles. This process is also a major degradation pathway for many aggregate-prone, disease-cau-sing proteins associated with neurodegenerative disorders, such as mutant huntingtin in Huntington’s disease. I | ỊFEBS Journal MINIREVIEW Huntington s disease degradation of mutant huntingtin by autophagy Sovan Sarkar and David C. Rubinsztein Department of MedicalGenetics University of Cambridge Cambridge Institute for MedicalResearch Addenbrooke s Hospital UK Keywords autophagy Huntington s disease lithium mTOR polyglutamine rapamycin Correspondence S. Sarkar Department of Medical Genetics University of Cambridge Cambridge Institute for MedicalResearch Addenbrooke s Hospital Hills Road Cambridge CB2 0XY UK Fax 44 1223 331206 Tel 44 1223 331139 E-mail ss457@ D. C. Rubinsztein Department of Medical Genetics University of Cambridge Cambridge Institute for MedicalResearch Addenbrooke s Hospital Hills Road Cambridge CB2 0XY UK Fax 44 1223 331206 Tel 44 1223 762608 E-mail dcr1000@ Received 29 February 2008 accepted 9 May 2008 doi Autophagy is a nonspecific bulk degradation pathway for long-lived cytoplasmic proteins protein complexes or damaged organelles. This process is also a major degradation pathway for many aggregate-prone disease-causing proteins associated with neurodegenerative disorders such as mutant huntingtin in Huntington s disease. In this review we discuss factors regulating the degradation of mutant huntingtin by autophagy. We also report the growing list of new drugs pathways that upregulate autophagy to enhance the clearance of this mutant protein as autophagy upregulation may be a tractable strategy for the treatment of Huntington s disease. Autophagy Degradation of cellular proteins occurs by two pathways. The proteasomes predominantly degrade shortlived nuclear and cytosolic proteins. These substrates are generally selected for degradation after they are tagged with polyubiquitin chains. The narrow pore of the proteasome precludes entry of protein complexes and organelles. The bulk degradation of cytoplasmic proteins or organelles is mediated largely by macroautophagy generally referred to as autophagy

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