Exp Mol Med.  2015 Mar;47(3):e147. 10.1038/emm.2014.117.

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

• Ciechanover A
• Kwon YT

• KMID: 2155412
• DOI: http://doi.org/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 beta-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.

MeSH Terms

Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism
Amyotrophic Lateral Sclerosis/drug therapy/metabolism
Animals
Autophagy/drug effects
DNA-Binding Proteins/metabolism
Humans
Huntington Disease/drug therapy/genetics/metabolism
Lysosomes/metabolism
Molecular Targeted Therapy
Mutation
Nerve Tissue Proteins/genetics/metabolism
Neurodegenerative Diseases/drug therapy/*metabolism
Parkinson Disease/drug therapy/metabolism
PrPSc Proteins/metabolism
Prion Diseases/drug therapy/metabolism
Proteasome Endopeptidase Complex/metabolism
Proteolysis
Proteostasis Deficiencies/metabolism
Superoxide Dismutase/metabolism
Ubiquitin/metabolism
alpha-Synuclein/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides
DNA-Binding Proteins
Nerve Tissue Proteins
PrPSc Proteins
Proteasome Endopeptidase Complex
Superoxide Dismutase
Ubiquitin
alpha-Synuclein
tau Proteins