Removing protein aggregates: the role of proteolysis in neurodegeneration: The role of proteolysis in neurodegeneration

D.A.T. Nijholt, L. de Kimpe, H.L. Elfrink, J.J.M. Hoozemans, W. Scheper

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74 Citations (Scopus)

Abstract

A common characteristic of neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's 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. © 2011 Bentham Science Publishers Ltd.
Original languageUndefined/Unknown
Pages (from-to)2459-2476
JournalCurrent medicinal chemistry
Volume18
Issue number16
DOIs
Publication statusPublished - Jun 2011

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