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Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominates.

ABSTRACT: Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression. We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that tau related changes largely resemble tau/TDP-43 changes. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE249339 | GEO | 2024/03/15

REPOSITORIES: GEO

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Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy

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2024-01-18 | GSE180672 | GEO

A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy

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2023-12-23 | GSE250255 | GEO

(CA)n oligonucleotides correct RNA mis-splicing in TDP-43 pathology (I)

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2023-09-28 | GSE244306 | GEO

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2020-10-20 | GSE153960 | GEO

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TDP-43, an ALS/FTD causal gene, regulates SREBF2-mediated cholesterol metabolism in the CNS

Project description:Maintaining cholesterol homeostasis is essential for health of all animal cells. Because of blood-brain barrier, de novo cholesetrol biosynthesis and intercellular cholesterol transport is thought to maintain cholesterol homeostasis within the central nervous system (CNS). Here, we showed that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), regulates SREBF2-mediated cholesterol metabolism in the central nervous system (CNS). Unbiased transcriptomic analysis of mice with oligodendroglial TDP-43 deletion revealed a progressive and pathway-wide disruption in the cholesterol metabolism correlating with reduced myelination and cholesterol level. Molecularly, TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins in the cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. Depletion of TDP-43 leads to reduced SREBF2 and cholesterol level in vitro and in vivo. The cholesterol reduction can be rescued by reintroducing either the nuclear portion of SREBF2 or LDLR, the latter of which is the receptor for cholesterol-containing low-density lipoproteins (LDLs). Furthermore, LDLR are observed to co-aggregate with pathological TDP-43 in oligodendrocytes of FTD patients and motor neurons of sporadic ALS patients. Taken together, our data indicates that TDP-43 is required to maintain SREBF2-dependent cholesterol homeostasis in the CNS, and disturbance of cholesterol metabolism may be involved in ALS, FTD and TDP-43 proteinopathies-related disease.

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