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Mus musculus

ABSTRACT: Frontal cortex transcriptomic analysis of a TDP-43 Q331K knock-in mouse [5month]

PROVIDER: PRJNA388188 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5617410_1.fastq.gz	Fastqsanger.gz
	SRR5617410_2.fastq.gz	Fastqsanger.gz
	SRR5617420_1.fastq.gz	Fastqsanger.gz
	SRR5617420_2.fastq.gz	Fastqsanger.gz
	SRR5617411_1.fastq.gz	Fastqsanger.gz

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Project description: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 droplets accumulation in primary fibroblast 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 post-mortem frontal cortex, gray 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.

Project description:A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and the accumulation of cytoplasmic inclusions of hyperphosphorylated TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs and ERVs are mobile genetic elements that constitute about 45% of our genome. These virus-like elements encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. Their expression is a proven source of DNA damage and inflammatory signaling. Research in Drosophila has demonstrated a causal role of RTEs/ERVs in mediating both intracellular toxicity of TDP-43 and the intercellular spread of these toxic effects from glia to neurons. RTEs and ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer’s Disease (AD) patients, as well as in cell culture in response to TDP-43 disruption, suggesting that the findings in Drosophila may be conserved across species. But the role of RTEs and ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. To investigate the functional contributions of RTEs in vertebrates, we utilized an established transgenic mouse model that overexpresses moderate levels of either human wild-type TDP-43 (hTDP-43-WT) or a mutant version with a specific causal amino acid substitution (hTDP-43-Q331K) associated with some inherited forms of the disease. Through RNA-sequencing of the motor cortex, and imaging of a LINE-1-EGFP retrotransposon indicator cassette, we found that the TDP-43 transgenic animals exhibit broad expression of RTEs and ERVs, along with replication of LINE-1 in glia and neurons in the motor cortex. This expression begins at the age of onset of neurological phenotypes, earlier in the hTDP-43-Q331K animals and much later in hTDP-43-WT. Although the motor defects progressively worsen over time, the LINE-1-EGFP replication reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms. These EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with non-cell autonomous effects on nearby neurons and glial cells.

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Mus musculus

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