Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Abstract

O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.

O-GlcNAc transferase suppresses necroptosis and liver fibrosis

“…Throughout the years it has become evident that dysfunction of O-GlcNAcylation sensitizes cells to various kinds of stress ultimately leading to cell death (24,25). This phenomenon has been repeatedly reported in various tissues and pathologies (26)(27)(28)(29), yet the mechanisms by which the perturbation of O-GlcNAcylation affects cell survival and death is undefined.…”

Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation

“…4,16–19 Indeed, studies of brain-specific OGT knockout mice point to a role for O-GlcNAc in neuronal function and neurodegeneration. 9,20–22 Liu et al reported higher levels of O-GlcNAc, OGT, and OGA in neurons compared to non-neuronal cells in the rat brain. 23 Maintaining high levels of O-GlcNAcylation prevents ectodermal differentiation of mouse ESCs, 13 impairs axonal branching, 24 and inhibits proteasome function.…”

Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus yet depresses neuronal output

“…Additionally, O-GlcNAcylation plays a crucial role in pathological states such as diabetes (Erickson et al, 2013;Vaidyanathan and Wells, 2014) where its elevation can contribute to disease pathogenesis, in epilepsy where increasing O-GlcNAc is protective (Sánchez et al, 2019;Stewart et al, 2017), and in neurodegeneration (Levine etal., 2019;Wang et al, 2016;Yuzwa and Vocadlo, 2014;Yuzwa et al, 2008Yuzwa et al, , 2012Yuzwa et al, , 2014aYuzwa et al, , 2014bZhu et al, 2014), where increasing O-GlcNAc can decrease pathological accumulation of phosphorylated tau or α-synuclein. Collectively, studies published by us and others suggest that maintaining proper balance in O-GlcNAcylation is critical to maintaining normal hippocampal function, as too much or too little O-GlcNAc has been linked to deficits in learning and memory (Taylor et al 2014;Wang et al 2016). Revealing the complex changes in neuronal and synaptic function induced by alterations in O-GlcNAcylation in non-pathological and pathological states will require further investigation.…”