Grant: Project Grant

Multiple sclerosis (MS) is a neurodegenerative disease that is highly prevalent in Canada. Many Canadians with MS experience severe disease progression. These individuals, usually bound to a wheelchair, often have genetic mutations that exacerbate their disease severity and progression and alter response to treatments. Remarkably, people with most severe form of MS (primary progressive MS) experience brain deficits during adolescence, when the brain is still developing. Yet, we do not understand whether and how gene mutations in people with severe MS affect brain development, and if these developmental perturbations lead to an altered response to a demyelinating injury later in life. Our previous work showed fractalkine receptor (CX3CR1) is a critical regulator of myelin formation in the developing and demyelinated brain. Notably, mutations in the CX3CR1 gene are associated with MS severity. Whether mutations in MS severity risk genes, like CX3CR1, affect CNS development and subsequent response to demyelinating injury later in life is unknown. This proposal is focused on the role of MS-associated CX3CR1 mutations in brain development (Objective 1), developmental origins of neurodegeneration in adulthood (Objective 2), as well as molecular mechanisms of CX3CR1 signalling (Objective 3). Our results may reveal developmental determinants of MS severity. This will contribute to our understanding of the molecular basis for MS disease heterogeneity, open a novel therapeutic time window and serve as a foundation for future development of therapeutics for MS patients with CX3CR1 mutations.