Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration. J Neurochem 2018 Jan;144(1):7-34
Date
10/20/2017Pubmed ID
29049853Pubmed Central ID
PMC5735008DOI
10.1111/jnc.14242Scopus ID
2-s2.0-85034243308 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
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.
Author List
Akan I, Olivier-Van Stichelen S, Bond MR, Hanover JAAuthor
Stephanie Olivier-Van Stichelen PhD Associate Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylglucosamineAnimals
Autophagy
Brain Chemistry
Caenorhabditis elegans Proteins
Cell Cycle
Cell Movement
Drosophila Proteins
Epigenesis, Genetic
Glycoproteins
Hexosamines
Humans
Intrinsically Disordered Proteins
Mammals
Mice, Knockout
Mitochondria
Models, Molecular
N-Acetylglucosaminyltransferases
Nerve Degeneration
Nerve Tissue Proteins
Neurogenesis
Protein Aggregation, Pathological
Protein Conformation
Protein Domains
Protein Isoforms
Proteostasis
beta-N-Acetylhexosaminidases
