Project R-13575

Getting a grip on slippery protein modifications in multiple sclerosis. (Research)

Increasing evidence indicates that fatty acid metabolism drives immune cell physiology in neuroinflammatory and autoimmune disorders such as multiple sclerosis (MS). To date, however, the culprit fatty acids and molecular mechanisms that govern their impact on immunity and disease pathology remain poorly understood. We recently demonstrated that subtle changes in cellular palmitate levels have a major impact on the disease-promoting and –resolving properties of immune cells in MS. Our exciting preliminary findings now indicate that S-palmitoylation (S-palm), an understudied posttranslational lipid modification that involves the binding of palmitate to proteins, is a strong driver of immunity and MS pathogenesis. We therefore hypothesize that S-palm drives the inflammatory and reparative properties of immune cells in MS. To address this, we aim to unravel changes in the palmitoyl-proteome and machinery associated with immune cell differentiation, and define if S-palm can be harnessed to suppress neuroinflammation and promote CNS repair. In addition, we will establish if MS patient-derived immune cells show perturbed S-palm, and identify the role of MS risk mutations herein. Findings from this project will unravel the therapeutic applicability of S-palm modulators to dampen (neuro)inflammation and stimulate CNS repair in MS.

01 January 2023 - 31 December 2024