Perturbation of O-GlcNAcylation, a nutrient sensing pathway, has been demonstrated in human Alzheimer's
disease (AD) brains, and inhibition of O-GlcNAcase (OGA) has been shown effective in inhibiting tau
phosphorylation in animal models. This proposal focusses on the protein O-GlcNAcylation and its impact on
neurological function and protein homeostasis. One of the key proteins we focus on is a-synuclein accumulation
which occurs prominently in Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson's
disease (PD), however, whether O-GlcNAcylation is involved in a-synuclein accumulation in vivo in mammalian
models has not been investigated. This is important because targeting a-synuclein is actively pursued as a
therapeutic strategy in treating neurodegenerative disease. In our preliminary studies, we have found that
inhibition of OGA increased autophagosomal and a-synuclein accumulation and attenuated autophagic flux in
primary neurons, cautioning a potential detrimental effect of inhibiting OGA, even though it was effective in
decreasing tau phosphorylation. In vivo, we have shown that key proteins involved in protein trafficking are
dynamically O-GlcNAcylated. In the proposed studies, we will test the hypothesis that sustained increase in
O-GlcNAc causes neurological dysfunction, thereby contributing to the pathogenesis of AD and DLB.
We have built a strong research team with expertise in O-GlcNAc biology, cutting-edge techniques of tag-mass
spectrometry and stoichiometry of O-GlcNAc modification, autophagy, and mouse models of tissue specific OGA
deficiencies. This study will: 1) Determine the impact of increased O-GlcNAc levels on neurological function in
vivo. 2) Determine the mechanisms through which O-GlcNAc modification impacts neurodegeneration. The
successful completion of these studies will establish a role for O-GlcNAcylation in regulating neurodegeneration,
and provide new mechanistic understanding of O-GlcNAc regulation of endolysosomal function, which will guide
strategies for neuroprotection. Completion of the proposed study will encourage future work introducing O-
GlcNAcylation site mimetic peptide as competitive inhibitors to test the potential benefits of preventing
detrimental O-GlcNAcylation while preserving beneficial O-GlcNAcylation. This proposal is directed at
addressing the urgent and pressing need to understand basic mechanisms of proteotoxicity in neurons and is
responsive to PAR-15-357 Understanding Alzheimer's Disease in the Context of the Aging Brain (R01).