TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects.

TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the TardbpM323K/M323K knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.