The laboratory of Rebecca Wallings, DPhil, was established in October of 2025 and investigates the role of an aging immune system, immune cell exhaustion and immunosenescence in brain health and the development of neurodegenerative diseases, such as Parkinson’s disease and Frontal Temporal Dementia (FTD). Her lab takes a multi-faceted approach in the laboratory that ranges from primary cell cultures, multiple preclinical mouse models, all the way to human biospecimens including plasma and peripheral blood mononuclear cells. This combination of human immune profiling and mechanistic research in preclinical models allows her lab's work to be highly translational and relevant to human disease — something that is central to the lab’s ethos. Her lab has a collaborative approach, appreciating that it “takes a village” to answer these complex questions, with extensive collaborations formed around the world both in and out of academia. The Wallings lab has multiple research projects studying the mechanisms by which immune cell exhaustion, chronic inflammation, an aging immune system and environmental risk factors that converge on the immune system contribute to neurodegenerative disease with the aim of identifying new therapeutic targets and potential biomarkers of disease risk. Their research is currently funded by multiple non-profit foundations and organizations.
Active Research
Although the role of immune dysfunction, both in the central nervous system and in the periphery, has become increasingly more appreciated as causative in neurodegenerative diseases over the last decade, to date there has been considerable neglect on the role of an aging immune system in these diseases. Immune cell exhaustion, which is characterized as a suppression of the immune response and immune cell function, is associated with both chronic inflammation as well as an aging immune system. Recent publications from Dr. Wallings have implicated PD-associated genetic mutations in the LRRK2 protein with increased risk of immune cell exhaustion in both preclinical models and clinical samples. The lab is currently funded by the Parkinson’s Foundation to extend these findings and investigate the potential protective effects of blocking immune cell exhaustion in preclinical models of LRRK2-PD, as well as investigating the role of lysosomal dysfunction and GCase enzymatic activity in both preclinical models and patient samples.
Dr. Wallings previously published findings that showed immune cells outside of the brain, which carry FTD-associated mutations, have a dampened or suppressed immune response. A dampened immune response is often associated with immune cell exhaustion and immunosenescence, when immune cells lose the ability to respond to infections and inflammation. This Brightfocus Foundation-funded project aims to investigate the downstream effects of I immune cell exhaustion in myeloid cells on immune cells within the adaptive immune system, and assess how immune cell exhaustion in the periphery contributes to degeneration and neuroinflammation in the presence of a western, high-fat, high-carbohydrate diet. The completion of this proposal will inform us of the role of an aging immune system in FTD and whether this is a potential therapeutic target. This is a highly novel approach given that inflammation has been viewed as rampant in neurodegenerative disease and should be dampened to be therapeutically beneficial. If our hypothesis is correct, and the immune system is indeed exhausted in FTD, alternative therapeutic approaches will need to be sought.
research team
Cassandra Cole
Lab Manager
Noelle Neighbarger
Laboratory Research Specialist
Jordan Weddle
Undergraduate Researcher
Henry Tehinshe Adetulubo
Undergraduate Researcher
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11/2025 – 10/2028 |
Bright Focus Standard Award Title: Investigating the role of immune cell exhaustion and gene-by-environment interactions in FTD Role: Principal Investigator |
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8/2024 – 8/2028 |
Launch Award, Parkinson’s Foundation Title: Investigating the effects of LRRK2 mutations on immune cell exhaustion Role: Principal Investigator
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- Laura P. Hughes*, Rebecca L. Wallings*, Roy N. Alcalay, Alicia Garrido, Malú Gámez Tansey, Nicolas Dzamko (2025). Interferon gamma stimulates coordinated changes in LRRK2, GCase and cathepsin activities in idiopathic and genetic Parkinson’s disease monocytes. NPJ Parkinson’s Disease. *co-first authorship
- Mark, J., Titus, A., Staley., H, Mahn, S., Alvarez, S., McFarland, N., Tansey, M. G*., & Wallings, R*. (2025). Peripheral immune cell response to stimulation stratifies Parkinson’s disease progression including prodromal cases. Communications Biology. *co-senior author.
- Rebecca L., Wallings, Drew A. Gillett, Hannah A. Staley, Savanna Mahn, Julian Mark, Noelle Neighbarger, Holly Kordasiewicz, Warren D. Hirst and Malú Gámez Tansey (2025). ASO-mediated knockdown of GPNMB in mutant-GRN and Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses. Molecular Neurodegeneration.
- Wallings, R. L., McFarland, K., Staley, H. A., Neighbarger, N., Schaake, S., Brueggemann, N., Zittel, S., Usnich, T., Klein, C., Sammler, E., & Tansey, M. G. (2025). The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner. Science Translational Medicine.
- Gillett, D., Neighbarger, N., Cole, C. L., Wallings, R. L.,* & Tansey, M. G.* (2024). Investigating the role and regulation of GPNMB in progranulin-deficient macrophages. *co-senior authors. Frontiers in Immunology.
- Gillett, D., Wallings, R. L., Huarte, O. U., & Tansey, M. G. (2023). Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease. Journal of Neuroinflammation. 20(1):286.
- Wallings, R. L., Mark. J., Staley, H. A., Drew A. Gillett., Neighbarger, N., Holly B. Kordasiewicz., Warren Hirst., & Tansey, M. G. (2023). ASO-mediated knockdown or kinase inhibition of G2019S-Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages. Molecular therapy – nucleic acids. 34:102064.
- Wallings, R. L.*, Hughes, L.*, Staley, H. A., Simon, Z.D., McFarland, N.R., Alcalay, R.N., Dzamko, N., & Tansey, M. G. (2022). WHOPPA enables parallel assessment of LRRK2 and GCase enzymatic activity in Parkinson’s disease monocytes. Frontiers in Cellular Neuroscience. 9:16:892899. *equal contributions.
- Tansey, M. G., Wallings, R. L., Herrick, M. K., Keating, C., & Joers, V., (2022). The role of neuroinflammation and immune dysfunction in Parkinson’s disease. Nature reviews immunology. 22, 657–673
- Wallings, R., Connor-Robson., N & Wade-Martins, R. (2019). LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Human Molecular Genetics, 28(16). 2696-2710.