Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.

Aging and Neurodegeneration: A Tangle of Models and Mechanisms.

Abstract: The research on aging and age-related diseases, especially the neurodegenerative diseases, is on the fast track. However, the results have so far not been translated to actual benefit for the patients in terms of treatment or diagnosis of age-related degenerative diseases including those of the CNS. As far as the prevention of the cognitive decline during non-pathological aging is concerned, there is nothing much to offer other than calorie restriction and physical exercise. Needless to say, the benefits are not up to our expectations. However, over the years at the experimental level it has been possible to identify several cellular and molecular mechanisms that are intricately associated with aging in general and neurodegenerative diseases in particular. These include oxidative stress and altered redox-signaling, mitochondrial dysfunction, inflammation, proteotoxicity and altered gene expressions. These inter-dependent pathways mediate cellular senescence and often culminate in programmed cell death like apoptosis and autophagy, and in the context of brain these changes are manifested clinically as cognitive decline and pathologically as neurodegeneration. This special issue provides the readers with glimpses of this complex scenario from different angles primarily in the context of brain and also attempts to identify the potential drug targets against neurodegenerative diseases.

Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity

Abstract: O-GlcNAcylation is an abundant post-translational modification implicated in human neurodegenerative diseases. We showed that loss-of-function of OGT (O-linked GlcNAc transferase) alleviated, while loss of OGA (O-GlcNAc selective β-N-acetyl-D-glucosaminidase) enhanced, the proteotoxicity of C. elegans neurodegenerative disease models including tauopathy, β-amyloid peptide and polyglutamine expansion. The O-GlcNAc cycling mutants act, in part, by altering insulin signaling, proteasome activity and autophagy. In mutants lacking either of these enzymes of O-GlcNAc cycling, there is a striking accumulation of GFP::LGG-1 (C. elegans homolog of Atg8 and LC3) and increased phosphatidylethanolamine (PE)-modified GFP::LGG-1 upon starvation. We speculate that O-GlcNAc cycling is a key nutrient-responsive regulator of autophagic flux acting at multiple levels including direct modification of BECN1 and BCL2.

Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.

Abstract: Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.

HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer.

Abstract: The strong clinical activity of the proteasome inhibitor bortezomib (Velcade) in multiple myeloma and other hematological malignancies has focused considerable attention on its mechanisms of action. Although NFκB inhibition was initially the mechanism in focus, accumulating evidence indicates that misfolded protein accumulation leading to proteotoxicity plays an even more important role in cell killing. Proteotoxicity that occurs as a consequence of protein aggregate accumulation has long been associated with the development of neurodegenerative diseases, and a large and growing body of literature has documented how protein aggregates are handled and disposed of via evolutionarily conserved mechanisms involving cross talk between the proteasome and autophagy in normal cells. The type II histone deacetylase HDAC6 plays important roles in these processes and HDAC6 inhibition enhances proteotoxicity. These observations served as the basis for the development of HDAC6-specific chemical inhibitors that are now being evaluated in combination with proteasome inhibitors in preclinical models. Nonetheless, there is also strong evidence that the more classical, chromatin-associated (type I) HDACs are also involved in the regulation of proteotoxicity, although the biochemical mechanisms underlying their effects are not well defined. Importantly, emerging evidence indicates that subsets of tumor cells contain defects in these protein quality control pathways, which may underlie their vulnerability to proteasome inhibitor-induced death. In addition, our clearer understanding of cytoprotective protein quality control responses is identifying novel candidate targets for therapeutic intervention. In this chapter, we present an overview of protein quality control mechanisms in normal tissues and describe how this information is informing our development of proteasome inhibitors and other agents that impact upon these pathways for cancer therapy.