Summary of Target and Rationale for Funding: O-GlcNAcase (OGA) is the enzyme responsible for removing O-GlcNAc, a noncanonical glycosylation post-translational modification, from proteins. A substantial body of Alzheimer’s disease (AD) literature supports a protective role for O-GlcNAcylation on tau. O-GlcNAc levels are reduced in AD patients and in preclinical AD models, and increased O-GlcNAcylation of tau is associated with reduced pathological tau phosphorylation. Pharmacologic inhibition of OGA has been shown to decrease tau pathology in multiple preclinical AD models, with emerging clinical evidence suggesting similar effects in patients.
Beyond tau, there is preliminary preclinical evidence that O-GlcNAc modification of α-synuclein may reduce its aggregation propensity. Consistent with this, OGA inhibitors have demonstrated promising preclinical efficacy in Parkinson’s disease (PD) models, although these effects are less definitive than those observed in AD and tauopathy models. OGA was prioritized through the Targets to Therapies (T2T) initiative in part because it is a highly druggable, clinical-stage target in CNS indications, with sufficient early evidence to support its potential repurposing for PD.
Key Gaps to Address: Repurposing OGA inhibitors for Parkinson’s disease is currently constrained by two key gaps: (1) an unclear safety profile associated with chronic OGA inhibition and (2) a lack of compelling evidence linking OGA/O‑GlcNAc biology to PD pathology in patient tissue.
Eli Lilly’s Phase 2 trial of an OGA inhibitor in early symptomatic Alzheimer’s disease did not meet its primary clinical endpoint and was associated with significant adverse events and study discontinuation. Because only a single molecule has been evaluated in a Phase 2 trial to date, a critical unresolved question for the field remains: what level of OGA inhibition is required to achieve therapeutic benefit while maintaining an acceptable tolerability profile?
Given that clinical adverse events are unlikely to be resolved through additional preclinical studies, T2T is not positioned to directly address this question. Instead, the field is awaiting safety data from Ferrer’s ongoing Phase 2/3 trial in progressive supranuclear palsy (PSP), expected in Q4 2026.
Beyond safety, the most significant bottleneck to advancing OGA inhibitors for PD is the absence of direct evidence linking alterations in OGA/O‑GlcNAc biology to disease in PD patients. To date, only a single study has examined total O‑GlcNAc levels in PD versus healthy control brain tissue, reporting a suggested increase in O‑GlcNAc in PD, findings that contrast with those observed in AD and were limited in depth. Additional studies are needed to strengthen the evidence base and to determine which proteins are affected, including whether α‑synuclein O‑GlcNAcylation is altered in PD.
Together, human O-GlcNAc tissue data and emerging clinical safety data will provide a critical go/no-go decision point for OGA in PD, informing whether this target should be advanced or deprioritized in favor of more promising therapeutic strategies.
Steps to Address Gaps: Through the Targets to Therapies (T2T) initiative, a collaborative team of OGA experts has been assembled to address a critical translational gap in Parkinson’s disease: the lack of compelling evidence linking OGA/O-GlcNAc biology to PD patient tissue. This T2T-funded project is specifically designed to close that gap by providing a definitive assessment of OGA biology in PD brain tissue. The proposal will quantify global O-GlcNAc levels and evaluate α-synuclein and tau O-GlcNAcylation, including site-specific α-synuclein O-GlcNAc modifications, in PD brain tissue. These analyses will leverage a combination of quantitative mass spectrometry, proteomics, and chemoenzymatic labeling approaches. In parallel, the study will measure phosphorylated S129 α-synuclein (pS129 αsyn) to directly test the relationship between α-synuclein O-GlcNAcylation and phosphorylation, analogous to what has been observed for tau. Together, these data will provide a rigorous, patient tissue-based framework for interpreting the impact of OGA modulation in Parkinson’s disease.
Matthew Pratt, Hsieh-Wilson, and Lance Wells: Multiscale measurement of O-GlcNAc changes in Parkinson’s Disease
OGA Tools for the community: In addition to addressing a key OGA scientific gap, T2T is also supporting projects focused on the validation and development of OGA research tools for the community. These efforts include knockout validation of existing commercial OGA antibodies, the generation of an antibody for α-synuclein O-GlcNAcylated at T72 (O-GlcNAc T72 α-synuclein) and the development of OGA knockout human induced pluripotent stem cell models. Visit the Research Tools Catalog to find these tools and more.