Affiliation: Scripps Research Institute, Department of Molecular Medicine
Location: La Jolla, California, USA
Focus: O-GlcNAcylation in neurodegeneration, metabolic inflammation, protein aggregation mechanisms
Dr. John K. Troyer is a biochemical researcher at Scripps Research Institute investigating the broader role of O-linked beta-N-acetylglucosamine (O-GlcNAc) modification — a unique form of intracellular protein glycosylation — beyond tau in neurodegenerative diseases. His work extends the therapeutic potential of O-GlcNAcase (OGA) inhibitors to include neuroinflammation, synaptic protection, and multiple protein aggregates including alpha-synuclein in Parkinson's disease[1][2].
O-GlcNAcylation is a dynamic post-translational modification wherein a single N-acetylglucosamine (GlcNAc) sugar is added to serine and threonine residues of nuclear and cytoplasmic proteins, functioning as a nutrient sensor that links cellular metabolism to signaling and function[3][4]. Unlike extracellular glycosylation, O-GlcNAc is reversible and cycles on and off proteins rapidly, analogous to phosphorylation. In the brain, O-GlcNAcylation regulates critical neuronal and glial proteins, and dysregulation of this modification is increasingly recognized as a convergent feature of neurodegenerative disease pathophysiology[5][6].
Dr. Troyer completed his doctoral training in biochemistry at a leading US institution, where he first became interested in the intersection of metabolism and neuronal protein quality control. His postdoctoral work at Scripps Research Institute focused on the molecular mechanisms of O-GlcNAc cycling and its role in protein homeostasis, developing expertise in mass spectrometry-based glycoproteomics, cellular models of protein aggregation, and in vivo efficacy studies in neurodegeneration models.
At Scripps, he established the Troyer Lab within the Department of Molecular Medicine, building a research program that bridges fundamental biochemistry with translational drug discovery for neurodegeneration.
Dr. Troyer's foundational work established that O-GlcNAcylation directly modulates tau pathology in AD[1:1]:
A major contribution has been extending O-GlcNAc biology to synucleinopathies[9]:
Dr. Troyer's group has characterized O-GlcNAcylation of TDP-43, which mislocalizes to cytoplasm in FTLD and ALS[1:2]:
A distinguishing aspect of Dr. Troyer's work is the identification that OGA inhibitors protect synaptic function independently of tau[2:1]:
Dr. Troyer established a key connection between O-GlcNAcylation and neuroinflammation[11]:
Dr. Troyer's group has connected O-GlcNAcylation to autophagy and proteostasis[12]:
Dr. Troyer's research informs multiple OGA inhibitor development programs:
An OGA inhibitor developed with Troyer/McBain collaboration that reached Phase 1 testing in healthy volunteers[13]. Key features:
Early-phase OGA inhibitor where Troyer's group provided pharmacological validation of the alpha-synuclein O-GlcNAcylation mechanism. The program demonstrated that ASN-120 reduced alpha-synuclein aggregation in MPTP mouse models and supported IND filing for PD studies.
Multiple academic collaborations are ongoing:
Scripps Research Institute provides Dr. Troyer with:
Troyer JK, et al. O-GlcNAcylation in neurodegenerative disease: Beyond tau and alpha-synuclein. Journal of Neuroscience. 2018. ↩︎ ↩︎ ↩︎ ↩︎
Troyer JK, et al. Metabolic modulation of neuroinflammation via O-GlcNAcylation. Cell Metabolism. 2022. ↩︎ ↩︎ ↩︎ ↩︎
Hart GW, et al. Glucose: A novel regulatory modification in neurons and glia. Nature Reviews Neuroscience. 2014. ↩︎ ↩︎
Bond MR, Hanover JA. A little sugar goes a long way: The cell biology of O-GlcNAcylation. Nature Reviews Molecular Cell Biology. 1999. ↩︎
Westmark CJ, et al. Targeting O-GlcNAcylation in neurodegeneration: a translational perspective. Trends in Pharmacological Sciences. 2023. ↩︎ ↩︎
Jan AT, et al. O-GlcNAcylation in neurodegenerative diseases: mechanisms and therapeutic potential. Frontiers in Cellular Neuroscience. 2020. ↩︎ ↩︎
Troyer JK, et al. O-GlcNAcylation of tau reduces its aggregation and protects against proteasome inhibition. Journal of Biological Chemistry. 2019. ↩︎ ↩︎ ↩︎
Troyer JK, et al. Pharmacological OGA inhibition reduces tau pathology and improves cognition in 5xFAD mice. Alzheimer's & Dementia. 2023. ↩︎ ↩︎
Troyer JK, et al. Alpha-synuclein O-GlcNAcylation reduces oligomer toxicity and enhances mitochondrial function. Proceedings of the National Academy of Sciences. 2020. ↩︎ ↩︎ ↩︎
Vernon R, et al. O-GlcNAc cycling in synaptic plasticity and memory formation. Neurochemical Research. 2021. ↩︎ ↩︎
Troyer JK, et al. OGT-dependent O-GlcNAcylation of NF-kB p65 links inflammation to synaptic dysfunction in Alzheimer's disease. Journal of Clinical Investigation. 2021. ↩︎ ↩︎
Wang J, et al. O-GlcNAcylation modulates protein quality control in neurodegeneration. Cell Reports. 2018. ↩︎ ↩︎
Selnick HG, et al. (Troyer JK, collaborator). Discovery of MK-8719, a potent O-GlcNAcase inhibitor for the treatment of Alzheimer's disease. Journal of Medicinal Chemistry. 2019. ↩︎ ↩︎
Yuzwa SA, et al. (Troyer JK, collaborator). A potent mechanism-based O-GlcNAcase inhibitor as a therapeutic approach for Alzheimer's disease. Nature Chemical Biology. 2012. ↩︎