Drosophila models of dementia uncover shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE217213 | GEO | 2024/05/09
REPOSITORIES: GEO
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Project description:TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.
2023-01-09 | GSE216294 | GEO
Project description:No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
2020-10-20 | GSE153960 | GEO
Project description:The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.
2023-09-28 | GSE244306 | GEO
Project description:Through splicing analysis of a publicly available RNA-Seq dataset, we discovered TDP-43 represses a cryptic exon splicing event in UNC13A, a gene that had been associated with FTD/ALS through GWA studies. To confirm the sequences of the cryptic exons, we used shRNA to reduce TDP-43 levels in iPSC-derived motor neurons (iPSC-MNs) and by amplicon sequencing the RT-PCR product, we observed the insertion in cells with TDP-43 depletion but not in control shRNA-treated cells. Through sequence alignment, we verified the sequences of the cryptic exons.
2021-12-04 | GSE182976 | GEO
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.
2021-07-01 | GSE133047 | GEO
Project description:Nuclear factor TDP-43 is known to play an important role in several neurodegenerative pathologies. In general, TDP-43 is an abundant protein within the eukaryotic nucleus that binds to many coding and non-coding RNAs and influence their processing. Using Drosophila, we have performed a functional screening to establish the ability of major hnRNP proteins to affect TDP-43 overexpression/depletion phenotypes. Interestingly, we observed that lowering hnRNP and TDP-43 expression has a generally harmful effect on flies locomotor abilities. In parallel, our study has also identified a distinct set of hnRNPs that is capable of powerfully rescuing TDP-43 toxicity in the fly eye (Hrb27c, CG42458, Glo and Syp). Most importantly, removing the human orthologs of Hrb27c (DAZAP1) in human neuronal cell lines can correct several pre-mRNA splicing events altered by TDP-43 depletion. Moreover, using RNA sequencing analysis we show that DAZAP1 and TDP-43 can co-regulate an extensive number of cellular pathways potentially important for the neuron biology. Our results suggest that changes in hnRNP expression levels can significantly modulate TDP-43 functions and affect pathological outcomes.
2017-05-31 | GSE97262 | GEO
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer.
2016-08-02 | GSE85065 | GEO
Project description:Transgenic (Tg) mice expressing nuclear or cytoplasmic human TDP-43 were generated. Tg mice had motor spasticity and forebrain neurodegeneration. Human TDP-43 reduced mouse TDP-43 in nuclei of affected neurons. Tg mice showed alterations in transcripts related to chromatin assembly.
2010-11-10 | GSE25182 | GEO
Project description:The human Tar-DNA-binding protein TDP-43 is closely associated with ALS and other neurodegenerative disorders. TDP-43 contains two highly conserved RNA-binding motifs and possesses a variety of documented roles in RNA metabolism, including pre-RNA splicing and repression of transcription. We sought to measure the effect that knockout and over-expression of the fly orthologue of this protein, Tar-DNA-binding protein homolog (TBPH), has on the transcriptome of the central nervous system (CNS) of Drosophila melanogaster. To this end, we used massively parallel sequencing methods (RNA-seq) to transcriptionally profile the CNS in loss-of-function mutants and gain-of-function over-expression genotypes. We found that loss of TBPH resulted in widespread gene activation, much of which could be reversed by rescue of TBPH expression, suggesting that repression is one of the major roles of TBPH. Conversely, we found that over-expression of TBPH resulted largely in decreased gene expression. However, there was little overlap in the genes which were affected in these two genotypes, suggesting that the bulk of genes affected by TBPH loss-of-function and over-expression are different. We provide a comprehensive look at enriched gene ontologies in both cases, suggesting that TDP-43 plays a role in regulating basic processes in neurons. We also describe a number of genes whose splicing is likely to be altered in the absence of TDP-43. In this study we compare the effects of knockout of the TDP-43 ortholog (TBPH) in the fly nervous system with the effects of its overexpression. 2 treatment groups are presented. In the first, TDP-43 knockout (G2) is compared to control (A1) and rescue (G2; TDP-43-GAL4>UAS-TDP-43). In the second comparison, the motor neuron driver D42-GAL4 is used to overexpress TDP-43 in motor neurons, using LacZ as a control for overexpression of a foreign protein.
2012-06-30 | E-GEOD-31194 | biostudies-arrayexpress