Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration

Author(s): D. A.T. Nijholt, L. De Kimpe, H. L. Elfrink, J. J.M. Hoozemans and W. Scheper

Volume 18, Issue 16, 2011

Page: [2459 - 2476] Pages: 18

DOI: 10.2174/092986711795843236

Price: $65

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


Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy