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Nutrient‐driven O ‐Glc NA c in proteostasis and neurodegeneration
Author(s) -
Akan Ilhan,
OlivierVan Stichelen Stephanie,
Bond Michelle R.,
Hanover John A.
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14242
Subject(s) - proteostasis , neurodegeneration , microbiology and biotechnology , biology , endoplasmic reticulum , diacylglycerol kinase , endoplasmic reticulum associated protein degradation , biochemistry , neurogenesis , autophagy , chemistry , unfolded protein response , phosphorylation , medicine , apoptosis , disease , protein kinase c , pathology
Abstract 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 ‐Glc NA c) regulates protein homeostasis. The O ‐Glc NA c 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 ‐Glc NA c transferase‐ and O ‐Glc NA case‐knockout alleles have helped define the role O ‐Glc NA c 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 ‐Glc NA c 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 ‐Glc NA c 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 ‐Glc NA c 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 ‐Glc NA c timer’ to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O ‐Glc NA c‐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 ‐Glc NA c in the physiology of the brain and its susceptibility to neurodegenerative injury.