Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

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

Язык: Английский