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The proteostasis network provides targets for neurodegeneration.

ABSTRACT: The production, quality control, and degradation of proteins are a tightly controlled process necessary for cell health. In order to regulate this process, cells rely upon a network of molecular chaperone proteins that bind misfolded proteins and help them fold correctly. In addition, some molecular chaperones can target terminally misfolded proteins for degradation. Neurons are particularly dependent upon this "proteostasis" system, failures in which lead to neurodegenerative disease. In this review, we identify opportunities for modulating molecular chaperone activity with small molecules, which could lower the burden of misfolded protein within neurons, reducing cell death and ameliorating the effects of neurodegeneration. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

SUBMITTER: Newton TM

PROVIDER: S-EPMC6715599 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The proteostasis network provides targets for neurodegeneration.

Newton Timothy Mark TM Duce James Alex JA Bayle Elliott David ED

British journal of pharmacology 20190523 18

The production, quality control, and degradation of proteins are a tightly controlled process necessary for cell health. In order to regulate this process, cells rely upon a network of molecular chaperone proteins that bind misfolded proteins and help them fold correctly. In addition, some molecular chaperones can target terminally misfolded proteins for degradation. Neurons are particularly dependent upon this "proteostasis" system, failures in which lead to neurodegenerative disease. In this r ...[more]

PMID: 30820936

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Project description:Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-GlcNAc transferase- and O-GlcNAcase-knockout alleles have helped define the role O-GlcNAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-GlcNAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-GlcNAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-GlcNAc cycling. Like the quality control system in the endoplasmic reticulum which uses a 'mannose timer' to monitor protein folding, we propose that cytoplasmic proteostasis relies on an 'O-GlcNAc timer' to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-GlcNAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-GlcNAc in the physiology of the brain and its susceptibility to neurodegenerative injury.

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The proteostasis network provides targets for neurodegeneration.

Publications

The proteostasis network provides targets for neurodegeneration.

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