# O-GlcNAc in protein homeostasis in the context of PD, AD and DLB

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

It is estimated that approximately 218,000 Veterans were diagnosed with dementia in 2017, and 423,000 new
cases of Alzheimer's disease and other dementias among military veterans in the decade ending in 2020.
Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson's disease (PD) are all contributors
to dementia which are associated with proteotoxicity; it is then critical to understand the mechanisms through
which toxic proteins form and why their removal from neurons is inadequate. The link(s) between proteotoxicity,
metabolism and the autophagy pathway, which removes toxic proteins, needs to be understood at a molecular
level and in the context of neurodegenerative disease. This proposal focuses on an understudied pathway that
is of interest in the sporadic degenerative diseases such as AD. In particular, perturbation of O-GlcNAcylation,
as 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. In light of
these putative beneficial effects of increasing O-GlcNAc levels, clinical trials have been initiated to evaluate the
efficacy of pharmacologically increasing this post-translational modification in treating AD. Whether the O-
GlcNAcylation pathway is tau specific or also engages other neurotoxic proteins, such as α-synuclein, has not
been fully investigated in a mammalian system. We are among the first to demonstrate that O-GlcNAcylation is
involved in α-synuclein accumulation in vivo in mammalian systems and serves as the principal focus of this
proposal. In support of this concept, we have shown that inhibition of OGA increased autophagosomal and α-
synuclein accumulation and attenuated autophagic flux in primary neurons. Our recent publication showing
that that protein O-GlcNAcylation is increased in PD patients also underlines the growing need to understand
the molecular regulation of this pathway. We have already developed the genetic animal models needed to test
the overall hypothesis of this proposal that a sustained increase in O-GlcNAc causes α-synuclein
accumulation and 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 in tag-mass
spectrometry of the O-GlcNAc modification, autophagy, and mouse models of tissue specific OGA deficiencies
and/or with α-synuclein overexpression. This study will: 1) Test the hypotheses that increasing neuronal O-
GlcNAc levels disrupts endogenous α-synuclein homeostasis and impairs neurological function, 2) Test the
hypothesis that O-GlcNAc modification of α-synuclein as well as autophagy/endolysosomal proteins both
contribute to α-synuclein accumulation and thereby contributing to neurodegeneration. The successful
completion of these studies will establish a role for O-GlcNAcylation in regulating α-synuclein homeo...

## Key facts

- **NIH application ID:** 9854735
- **Project number:** 5I01BX004251-02
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Jianhua Zhang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854735

## Citation

> US National Institutes of Health, RePORTER application 9854735, O-GlcNAc in protein homeostasis in the context of PD, AD and DLB (5I01BX004251-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854735. Licensed CC0.

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