Splicing repression is a major function of TDP-43 in motor neurons

Donde, Aneesh; Sun, Mingkuan; Ling, Jonathan P.; Braunstein, Kerstin E.; Pang, Bo; Wen, Xinrui; Cheng, Xiao; Chen, Liam; Wong, Philip C.

doi:10.1007/s00401-019-02042-8

Cited by 69 publications

(55 citation statements)

References 68 publications

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“…Two groups found that the number of synaptic boutons and axonal branches was reduced [ 267 , 280 ], while another group found that both increased [ 265 ]. Four other studies did not detect any alteration in bouton and axonal branch numbers at the NMJs [ 159 , 266 , 277 , 281 ].…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…To go further, the authors used a chimeric construct consisting of the N-terminal region of TDP-43, including the two RNA-binding domains, fused to the splicing repressor ribonucleoprotein, PTB-binding 1 (RAVER1) (TDP-43 Nter -RAVER1). When TDP-43 Nter -RAVER1 was expressed in motoneurons of TBPH mutants, it highly extended lifespan [ 280 ]. On the contrary, the TDP-43 Nter -RAVER1 construct carrying two mutations in the RRM1 that abolish RNA binding had no effect [ 280 ].…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…When TDP-43 Nter -RAVER1 was expressed in motoneurons of TBPH mutants, it highly extended lifespan [ 280 ]. On the contrary, the TDP-43 Nter -RAVER1 construct carrying two mutations in the RRM1 that abolish RNA binding had no effect [ 280 ]. This confirms that the protective effect of TDP-43 Nter -RAVER1 was due to TDP-43 binding onto its target genes.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

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Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

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Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

See 1 more Smart Citation

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…8,27,28 Transgenic mice expressing human TDP-43 with a mutated NLS displayed neuronal loss and tract degeneration in association with the downregulation of endogenous nuclear TDP-43 but with sparse cytoplasmic inclusions; this fact suggests that a loss of nuclear TDP-43, rather than cytoplasmic inclusions, is correlated with neuronal dysfunctions. 15 Experiments with conditional depletion or knockout models of TDP-43 have shown ALS-like clinical phenotypes 29 and cellular dysfunctions including deficits in DNA repair, 30 an alteration of TDP-43-related transcriptome resulting in synaptic abnormality, 31 a loss of splicing repressor function, 32 and astrocytic activation. 33…”

Section: Als-tdp and Ftld-tdpmentioning

confidence: 99%

Reappraisal of the anatomical spreading and propagation hypothesis about TDP‐43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Riku

2020

Neuropathology

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Neuronal inclusion of transactivation response DNAbinding protein 43 kDa (TDP-43) is known to be a pathologic hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43, which is physiologically a nuclear protein, is mislocalized from the nucleus and aggregated within the cytoplasm of affected neurons in ALS and FTLD patients. Neuropathologic or experimental studies have addressed mechanisms underlying spreading of TDP-43 inclusions in the central nervous system of ALS and FTLD patients. On the basis of postmortem observations, it is hypothesized that TDP-43 inclusions spread along the neural projections. A centrifugal gradient of TDP-43 pathology in certain anatomical systems and axonal or synaptic aggregation of TDP-43 may support the hypothesis. Experimental studies have revealed cell-to-cell propagation of aggregated or truncated TDP-43, which indicates a direct transmission of TDP-43 inclusions to contiguous cells. However, discrepancies remain between the cell-to-cell propagation suggested in the experimental models and the anatomical spreading of TDP-43 aggregations based on postmortem observations. Transsynaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of transsynaptic transmission of aggregated proteins remain to be elucidated. Moreover, the spreading of TDP-43 inclusions varies among patients and genetic backgrounds, which indicates host-dependent factors for spreading of TDP-43 aggregations. Perturbation of cellular TDP-43 clearance may be a possible factor modifying the aggregation and spreading. This review discusses postmortem and experimental evidence that address mechanisms of spreading of TDP-43 pathology in the central nervous system of ALS and FTLD patients.

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“…In vivo studies have revealed that TDP-43 regulates its splicing mechanism via its C-terminal glycine-rich domains [76]. A recent study of TDP-43 knockdown in a Drosophila model expressing chimeric repressor proteins demonstrated that TDP-43 in motor neurons regulates RNA splicing fidelity through splicing repression [77]. These findings are in agreement with previous studies reporting TDP-43's interaction with more than 6000 mRNAs in the mouse brain and TDP-43 depletioninduced altered splicing of ~900 mRNAs causing neuronal vulnerability ( Figure 2) [78].…”

Section: Rna Transactionsmentioning

confidence: 99%

The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis

Mitra

Hegde²

2020

Amyotrophic Lateral Sclerosis - Recent Advances and Therapeutic Challenges

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The pathology of the RNA-/DNA-binding protein TDP-43, first implicated a decade ago in the motor neuron disease amyotrophic lateral sclerosis (ALS), has been subsequently linked to a wide spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer's disease (AD), and related dementia-associated disorders. ALS, also known as Lou Gehrig's disease, is a progressive, degenerative motor neuron disorder, characterized by a diverse etiopathology. TDP-43 pathology, mediated by a combination of several mutations in the TARDBP gene and stress factors, has been linked to more than 97% of ALS patients. We recently identified, for the first time, the critical involvement of TDP-43 in neuronal genome maintenance and the repair of DNA double-strand breaks (DSBs). Our studies showed that TDP-43 regulates the DNA break-sealing activities of the XRCC4-DNA Ligase 4 (LIG4) complex in DSB repair, suggesting that loss of genomic integrity in TDP-43-associated neurodegeneration may be amenable to a DNA repair-based intervention. In this chapter, we discuss the broader aspects of TDP-43 toxicityinduced pathomechanisms, including the emerging role of TDP-43 in neuronal DSB repair and its synergistic genotoxic effects with other neurodegeneration-associated etiologies that contribute significantly to neuronal dysfunction. We also discuss potential future perspectives and underscore how unraveling the molecular basis and implications of TDP-43-induced genome instability in ALS could guide the development of neuroprotective therapies.

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Splicing repression is a major function of TDP-43 in motor neurons

Cited by 69 publications

References 68 publications

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Reappraisal of the anatomical spreading and propagation hypothesis about TDP‐43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis

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