Summary of Target and Rationale for Funding: NOD2 is a signaling protein that plays a central role in regulating immune and inflammatory pathways. Preliminary genetic data suggest a potential link between NOD2 and Parkinson’s disease (PD). Early studies in PD patient samples indicate that NOD2 expression or activity may be dysregulated. Functional studies in cellular and pre-clinical models further suggest that reducing NOD2 activity can rescue PD-associated phenotypes. Given its well-established role in Crohn’s disease and other inflammatory disorders —where it is already being pursued as a therapeutic target— NOD2 represents a compelling novel candidate for therapeutic exploration in PD. MJFF funding through the Targets to Therapies Initiative (T2T) was provided to systematically de-risk NOD2 as a PD target by clarifying its genetic, molecular and functional contributions to disease pathophysiology.
Key Gaps to Address: Given the novelty of NOD2 as an emerging therapeutic target, several key gaps must be addressed to enable its translation into potential therapies forPD. First, the landscape of NOD2 genetic variants associated with PD risk or protection and their mechanistic impact on disease biology, remains unresolved, leaving it unclear whether activation or inhibition of NOD2 signaling would be therapeutically beneficial. Second, data directly linking NOD2 to PD pathogenesis in patient samples are limited and assays to monitor NOD2 activity in PD tissues and patient-derived cells are lacking. Third, few high-quality tool compounds are available to modulate NOD2 activity, limiting the ability to assess the effects of its activation or inhibition and hindering early-stage therapeutic exploration. Finally, there is a shortage of data exploring the role of NOD2 in PD-relevant models, whether through genetic manipulation or pharmacological modulation. To date, the efficacy of NOD2-targeting small molecules has not been evaluated in Parkinson’s disease models.
Steps to Address Gaps: Through the T2T, a diverse team of investigators has been assembled to fill critical knowledge and resource gaps surrounding NOD2 in PD. These projects comprehensively address existing deficiencies by integrating expertise in genetics, immunology, NOD2 biology, chemical biology,and translational neuroscience. The team is clarifying the directionality and impact of known PD-associated NOD2 variants and identifying new ones; characterizing NOD2 expression and signaling in PD patient tissues and microbiota; evaluating NOD2 agonists and antagonists using structural and cellular assays; testing whether NOD2 knockout can rescue PD phenotypes in alpha-synuclein models; and assessing whether NOD2 activation can mitigate PD-related pathology. Collectively, these efforts represent a coordinated and complementary approach to de-risking NOD2 as a therapeutic target and advancing it toward translational readiness.
GAP 1: Clarifying the directionality of PD-associated NOD2 variants and identifying new ones
- Virginie Buggia-Prevot: Using Knowledge Graphs to Predict NOD2 Directionality for Therapeutic Effect in Parkinson’s Disease
- Inga Peter, Towfique Raj, Yuval Itan: Characterizing the NOD2 Genetic Landscape Driving Risk and Protection in Parkinson’s Disease
GAP 2: Characterizing NOD2 expression and signaling in PD patient tissues and microbiota
- Justine Tigno-Aranjuez, Ruth Napier: Inflammatory and Regulatory Functions of NOD2 in the Setting of Parkinson’s Disease
- Dana Philpott: Modulating Levels of NOD2 Ligands in the Gut Microbiota to Dampen Neuroinflammation in Parkinson’s Disease
GAP 3: Evaluating NOD2 agonists and antagonists through structural and cellular assays
- Howard C. Hang, Hao Wu: Development and Validation of Synthetic NOD2 Modulators for Parkinson’s Disease
GAP 4: Testing NOD2 modulation in vivo using α-synuclein models
- Stephen E. Girardin: Assessing the Role of NOD2 in Murine Models of Parkinson’s Disease
- Abid Oueslati, Serge Rivest: Investigating whether NOD2 Activation can Reduce Alpha-synuclein Aggregation and Toxicity in Cellular and Pre-clinical Models of Parkinson’s Disease
NOD2 Tools for the Community: In addition to addressing key NOD2 scientific gaps, T2T is also supporting projects focused on the validation and development of NOD2 research tools for the community. These efforts include knockout validation of existing commercial NOD2 antibodies, the generation of new high-quality NOD2 antibodies and the development of NOD2 knockout cellular models. Visit the Research Tools Catalog to find these tools and more.