Proteasomal dysfunction in aging and Huntington disease

• Type of Material: Article
• Authors: Xiao-Jiang Li, Emory University; Shihua Li, Emory University
• Language: English
• Date: 2011-07
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2010.11.018
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 43
• Issue: 1
• Start Page: 4
• End Page: 8
• Grant/Funding Information: We would like to acknowledge the support of several NIH grants (AG109206, NS036232, NS041669 to X.J.L.) and (NS045016 and AG031153 to S.H. L.).
• Keywords: ubiquitin; Huntingtin; proteasome; polyglutamine; aging; autophagy
• Research Categories: Biology, Neuroscience; Biology, Genetics; Health Sciences, Pathology

Abstract

Protein degradation plays a central role in many cellular functions. Misfolded and damaged proteins are removed from the cells to avoid toxicity. Eukaryotic cells have two main routes for clearing misfolded or toxic proteins: the ubiquitin-proteasome and autophagy-lysosome pathways. The ubiquitin-proteasome system (UPS) is ubiquitously present in the cytoplasm, nucleus, and various subcellular regions whereas autophagy predominantly functions in the cytoplasm. The activity of the UPS often remains at a high level, whereas basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic functions. Because of the presence of the UPS in the nucleus, the UPS function may be more important for clearing misfolded proteins in the nucleus. Polyglutamine diseases, including Huntington disease (HD), show the age-dependent neurological symptoms and the accumulation of misfolded proteins that are often found in the nucleus. The selective neuropathology in HD is also found to associate with the preferential accumulation of the disease protein huntingtin in neuronal cells. Although it is clear that the UPS is important for clearing mutant huntingtin, it remains unclear whether aging or HD affects the capacity of neuronal UPS to remove toxic and misfolded proteins. In this review, we focus on the relationship between the UPS function and aging as well as Huntington disease. We also discuss findings that suggest that aging is a more important factor that can negatively impact the function of the UPS.