Abstract
A common characteristic of neurodegenerative diseases like Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, the proteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and the autophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain the proteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activated by disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways are affected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in different neurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differences have important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS and autophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.
Keywords: Autophagy, α-synuclein, neurodegeneration, polyglutamine disorders, proteostasis, tau, ubiquitin proteasome system, unfolded protein response
Current Medicinal Chemistry
Title: Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration
Volume: 18 Issue: 16
Author(s): D. A.T. Nijholt, L. De Kimpe, H. L. Elfrink, J. J.M. Hoozemans and W. Scheper
Affiliation:
Keywords: Autophagy, α-synuclein, neurodegeneration, polyglutamine disorders, proteostasis, tau, ubiquitin proteasome system, unfolded protein response
Abstract: A common characteristic of neurodegenerative diseases like Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, the proteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and the autophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain the proteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activated by disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways are affected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in different neurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differences have important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS and autophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.
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Cite this article as:
A.T. Nijholt D., De Kimpe L., L. Elfrink H., J.M. Hoozemans J. and Scheper W., Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration, Current Medicinal Chemistry 2011; 18 (16) . https://dx.doi.org/10.2174/092986711795843236
DOI https://dx.doi.org/10.2174/092986711795843236 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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