O-linked N-acetylglucosamine protein modification in mouse models of neurodegenerative diseases

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Thesis type
(Thesis) Ph.D.
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The O-linked addition of β-N-acetylglucosamine to proteins (O-GlcNAc) is a form of intracellular glycosylation that has gained increasing attention for its potential involvement in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). ALS has several causes including abnormal phosphorylation of neuronal proteins as well as several gene mutations including those in the sod1 gene, which encodes superoxide dismutase 1, as well as the TARDBP gene, which encosed TDP-43. Abnormally elevated phosphorylation of proteins including TDP-43, neurofilaments, and tau are all implicated in neurodegeneration. Tau, for example, forms intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. O-GlcNAc transferase (OGT) catalyzes the installation of GlcNAc onto specific serine and threonine residues of target proteins, while O-GlcNAcase (OGA) removes the modification. It is known that O-GlcNAc modification of tau and other proteins is reciprocal to phosphorylation. The objective of this thesis was to improve our understanding of the role that O-GlcNAc has on proteins implicated in neurodegeneration in animal models of ALS and AD. The main findings are (1) O-GlcNAc levels were reduced in spinal cord tissue from the mSOD mouse model of ALS specifically in motor neurons; (2) mislocalization of TDP-43 occurs in aged mSOD mice; (3) mouse brain TDP-43 was found to be O-GlcNAc modified and four O-GlcNAc modification sites were mapped on recombinant full-length human TDP-43; (4) OGA inhibitor Thiamet-G treatment to JNPL3 mouse model of AD increased tau O-GlcNAc modification, hindered tau aggregation, and protected mice against neuronal cell loss. These results suggest that the neurodegeneration found in mSOD mice might be associated with a reduction of O-GlcNAc levels in motor neurons, and O-GlcNAc modification might influence the abnormal phosphorylation of TDP-43 in ALS. These studies also provide new insight into the potential association of SOD1 and TDP-43, and offer support for OGA as a viable therapeutic targets that might provide an opportunity to alter disease progression in AD and offer benefits in other diseases characterized by the aggregation of proteins that can be O-GlcNAc modified.
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Supervisor or Senior Supervisor
Thesis advisor: Vocadlo, David
Thesis advisor: Krieger, Charles
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