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

Aaron Ciechanover,Yong Tae Kwon

doi:10.1038/emm.2014.117

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.

Highlights

Misfolded proteins generated in various cellular compartments, including the cytoplasm, nucleus and endoplasmic reticulum (ER), are efficiently removed by quality control systems composed of the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy (Figure 1).[1]
The disease-causing misfolded proteins are generated over the course of aging by post-translational modifications of native proteins or genetic mutations of otherwise non-pathogenic proteins
These pathogenic agents tend to aggregate into oligomers with enriched βsheet content, which can further grow into fibrillar inclusion bodies or extracellular plaques, serving as clinical hallmarks of many neurodegenerative diseases. β-Sheet-enriched aggregates can impair—either directly or indirectly—the UPS as well as CMA and macroautophagy by interacting with various cellular molecules, including key components of proteolytic pathways

Summary

Introduction

Misfolded proteins generated in various cellular compartments, including the cytoplasm, nucleus and endoplasmic reticulum (ER), are efficiently removed by quality control systems composed of the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy (Figure 1).[1].

Results

Conclusion