Project Details
Projekt
Dissecting the functional consequences of Multiple Sclerosis risk variants in neurons
Applicant
Dr. Jessy Chen
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 558942519
Multiple sclerosis (MS) exhibits significant heterogeneity in relapse frequency, disability progression and response to treatment. The complex molecular and cellular basis of MS heterogeneity, and in particular the neurodegenerative aspect of MS, remains a challenge to the scientific community. Inflammatory processes, initially driven by peripheral immune cells invading the central nervous system (CNS), lead to demyelination. Disease progression includes a gradual accumulation of peripheral and CNS immune cells within the connective tissue spaces of the brain. Next to inflammation, neuroaxonal damage is also driven by metabolic dysfunction like disrupted ion channel distribution and mitochondrial dysfunction contributing to neurodegeneration. However, the role of neuronal susceptibility in the pathogenesis of MS remains unclear. Genome-wide association studies (GWAS) have described >234 known genetic susceptibility variants and, more recently, 1 MS severity variant, each marked by a single nucleotide polymorphism (SNP). In most cases, the affected gene and cell type have not been definitively identified. In a new multi-ancestry GWAS meta-analysis the De Jager laboratory investigated over 276 MS susceptibility variants, 45 of which are new in the preliminary analysis. They integrated these results with those from a brain single nucleus RNAseq expression quantitative loci (eQTL) and published results from peripheral blood mononuclear cells (PBMCs). Colocalisation analysis was performed to assess whether a single variant influences both expression and susceptibility to MS. Interestingly, among CNS cells, inhibitory neurons showed the most unique colocalisations (18 SNPs). We propose to characterize the role of neurons in MS propagation using the high-dimensional datasets of human postmortem brain (Aim 1 and 2) from the NMSS Brain Bank and other collaborating brain banks, and functional assays in induced pluripotent stem cell (iPSC)-derived inhibitory neuron cultures (Aim 3). We will study chromatin accessibility in neuronal and glial cells to understand how these SNPs alter RNA expression. Also, we will use proteomic data from MS and non-MS neurodegenerative brain tissue to study spread at the proteome level. By combining gene expression, chromatin accessibility and proteomic data, we will investigate the effects of the MS severity variant in parallel. Aim 2 and 3 of the project focus on functional consequences of neuronal MS variants to the microenvironment in brain tissue (using the Xenium platform by 10x Genomics) and in iPSC derived CRISPR modulated inhibitory neuron cell culture models. Thereby, we intent to explore the causal chain of molecular events that emerge from each MS-associated polymorphism. We aim to contribute to the identification of new targets for biomarkers or drug targets in association with neurodegenerative aspects of MS.
DFG Programme
WBP Fellowship
International Connection
USA
