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Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies

A. Ciechanover,Y. Kwon

Published 2015 in Experimental and Molecular Medicine

ABSTRACT

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons. Strategies for speeding up the removal of misfolded proteins could counter the devastating effects of various neurological disorders. Cells have many ways of ‘taking out the garbage’, but these can become impeded in diseases such as Alzheimer's, where brain cells accumulate toxic clumps of misfolded proteins. Aaron Ciechanover and Yong Tae Kwon of Seoul National University in South Korea review how these clearance pathways get thwarted in neurodegenerative conditions associated with protein aggregation. Cellular quality control mechanisms deteriorate with age. However, some diseases directly interfere with cellular machinery. For example, in Parkinson's disease, aggregates of the α-synuclein protein cause ‘traffic jams’ in a cellular mechanism responsible for eliminating misfolded proteins. Drugs that selectively stimulate these removal processes offer hope, and the authors highlight promising early data from animal studies.

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