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.

authors

Wang AC,Jensen EH,Rexach JE,Vinters HV,Hsieh-Wilson LC

doi

10.1073/pnas.1606899113

subject

Has Abstract

pub_date

2016-12-27 00:00:00

pages

15120-15125

issue

52

eissn

0027-8424

issn

1091-6490

pii

1606899113

journal_volume

113

pub_type

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