TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects

Reviewed as evidence on: Cerebral amyloid angiopathy and 5-year dementia risk 2 studies (what the news said). Being listed means the study bears on the question, not that it agrees with the news.

Topic: Brain proteins, microglia and lab models

Abstract 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 Tardbp M323K/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.

Key findings

• 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.
• Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.

Why it matters

In a TDP-43 knock-in mouse model and postmortem FTLD-TDP tissue, TDP-43 dysfunction was linked to altered cholesterol-related lipid pathways, lipid droplet accumulation and myelination defects. This is laboratory and tissue research describing a disease mechanism, not a treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1007/s00401-025-02927-x
• PubMed: 40906043
• Original source →
• Free full text: Acta Neuropathologica →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{garciatoledo2025-40906043,
  author  = {García-Toledo, Irene and Godoy-Corchuelo, Juan Miguel and Fernández-Beltrán, Luis C. and Ali, Zeinab and Guindo-Arroyo, Ariadna and Jiménez-Coca, Irene and Jiménez-Rodríguez, Jesús and Javaloyes-García, Karen and others},
  title   = {{TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects}},
  journal = {Acta Neuropathologica},
  year    = {2025},
  doi     = {10.1007/s00401-025-02927-x},
  pmid    = {40906043},
  url     = {https://doi.org/10.1007/s00401-025-02927-x}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia

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