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Dynamic Role of Ubiquitination in the Management of Misfolded Proteins Associated with Neurodegenerative Diseases

  • Chapter
Protein Folding and Misfolding: Neurodegenerative Diseases

Part of the book series: Focus on Structural Biology ((FOSB,volume 7))

Abstract

Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Although a subject of intense research, how misfolded proteins bypass sophisticated protein quality control measures in the cell to be deposited as ubiquitin-enriched inclusion bodies remains poorly understood. Whilst proteasome dysfunction could account for this phenomenon, emerging evidence suggests otherwise. We have previously hypothesized that under conditions of proteolytic stress, the cell may switch to a non-proteolytic form of ubiquitination to help divert misfolded proteins away from an overloaded proteasome. In this way, the cell could preserve its proteasome function over prolonged periods of stress and recover thereafter. Supporting this, we recently found that non-proteolytic lysine (K) 63-linked ubiquitin modification promotes the formation of protein inclusions associated with several major neurodegenerative diseases. Importantly, we further found that K63-linked polyubiquitin selectively facilitates the subsequent clearance of inclusions via autophagy. In this chapter, we will discuss the apparent dynamic role of ubiquitination in the management of misfolded proteins.

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Authors and Affiliations

  1. Neurodegeneration Research Lab National Neuroscience Institute Singapore and Department of Anatomy and Structural Biology Marion Bessin Liver Research Center, Albert Einstein College of Medicine, USA

    Kah-Leong Lim

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  1. Esther S. P. Wong
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  2. Jeanne M. M. Tan
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  3. Kah-Leong Lim
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  1. Hungarian Academy of Sciences, Biological Research Center Institute of Enzymology, Karolina út 29, 1113, Budapest, Hungary

    Judit Ovádi  & Ferenc Orosz  & 

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Wong, E.S.P., Tan, J.M.M., Lim, KL. (2009). Dynamic Role of Ubiquitination in the Management of Misfolded Proteins Associated with Neurodegenerative Diseases. In: Ovádi, J., Orosz, F. (eds) Protein Folding and Misfolding: Neurodegenerative Diseases. Focus on Structural Biology, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9434-7_3

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