Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Background Myelin associated oligodendrocyte basic protein ( MOBP ) is an abundantly expressed oligodendrocyte gene. Genetic variation at the MOBP locus has been associated with risk for multiple neurodegenerative disorders, including progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. Methods We assessed genetic overlap and colocalisation at the MOBP locus across multiple neurodegenerative diseases. Disease-associated signals were fine-mapped to prioritise putative causal variants, and the strongest signals were subsequently investigated using molecular quantitative trait loci and post-mortem brain tissue datasets. Results ALS and PSP showed strong genetic association at MOBP , with highly overlapping associated variants and strong evidence that both diseases share the same causal signal. Overlap with frontotemporal dementia was weaker. Methylation quantitative trait locus colocalisation identified cg15069948, located near an exon junction within MOBP , as strongly colocalising with the ALS and PSP genetic risk signals. In PSP brain tissue, carriers of the rs1768208-T risk allele showed lower methylation at cg15069948. We additionally identified evidence for an interaction between rs1768208 genotype and cg15069948 methylation associated with altered MOBP 3′ untranslated region architecture. Conclusions These findings identify a shared ALS/PSP genetic–epigenetic mechanism at MOBP that is distinct from promoter-associated dysregulation in MSA. Together, they position MOBP as a key oligodendrocyte regulatory locus with both shared and disea e-specific roles in neurodegeneration.
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: BrightFocus Foundation, CurePSP, Target ALS, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Tau Consortium, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Reta Lila Weston Trust for Medical Research
Awards: The impact of Alzheimer's disease susceptibility alleles on microglia transcriptome, Learning the Regulatory Code of Alzheimer's Disease Genomes, G3571804645, The role of peripheral myeloid cells in Alzheimers disease, Unraveling the Role of Clonal Hematopoiesis in Neurodegenerative Diseases, Big Omics Data Engine 2 Supercomputer, Modeling the impact of regulatory and splicing variants on cellular function in Alzheimer's disease, DTP Bid Led by University College London, COVID and Translational Science supercomputer (CATS), Conduits: Mount Sinai Health System Translational Science Hub, Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets, Novel artificial intelligence-based approaches to understand the pathological and genetic drivers of primary tauopathies, Mount Sinai Alzheimer's Disease Research Center, Modeling the impact of regulatory and splicing variants on cellular function in Alzheimer's disease, The Role of Myeloid Cells in Parkinson's Disease, Genetic determinants of TF binding in pooled microglia
OpenAlex ID: W7141512504