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

AbstractNuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression inDrosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Discussion Benign fasciculations are very common and occur in up to 70% of the general population. They occur at different points in people’s lives. They can be brought out by stress, poor sleep hygiene and caffeine. Caffeine has numerous uses especially for regulating sleep and attention. However too much can cause restlessness, jitteriness and sleep deprivation too. The recommended amount of caffeine for a teenager is
Source: PediatricEducation.org - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
AbstractBackgroundRespiratory failure represents an unavoidable step in patients with amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND). The development of diaphragm ultrasonography (DUS) provides an alternative useful and risk-free tool to supply clinical, functional, and neurophysiological assessment of respiratory muscle weakness. Our aim was to evaluate if sonographic changes (thickness and echogenicity in the costal portion of the diaphragm, at rest and during respiratory movements) may be used in ALS patients to assess disease severity over time, to rule out any risk or discomfort due to tradi...
Source: Neurological Sciences - Category: Neurology Source Type: research
Authors: Ralli M, Lambiase A, Artico M, de Vincentiis M, Greco A Abstract BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neur...
Source: The Israel Medical Association Journal - Category: General Medicine Tags: Isr Med Assoc J Source Type: research
This article is protected by copyright. All rights reserved. PMID: 31509351 [PubMed - as supplied by publisher]
Source: Anatomical Record - Category: Anatomy Authors: Tags: Anat Rec (Hoboken) Source Type: research
CONCLUSION The Turkish versions of the ALSAQ short and long forms are valid and reliable tools to be used in the assessment of the quality of life in ALS patients.
Source: Journal of Neuroscience Nursing - Category: Neuroscience Tags: Article Source Type: research
Conclusion: Total oral transit time in MND varies within the same food consistency and the longer the TOTT, regardless of food consistency, the lower the functional performance in MND.RESUMO O comprometimento na fase oral da degluti ção na doença do neurônio motor (DNM) é ocasionado por fraqueza, fasciculação e atrofia de língua, podendo comprometer o tempo de trânsito oral (TTO) e o tempo total de alimentação. Objetivo: Descrever e relacionar o tempo de trânsito oral total (TTOT) com o desempenho funcional na DNM em distintas consistênc...
Source: Arquivos de Neuro-Psiquiatria - Category: Neurology Source Type: research
CONCLUSIONS: RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously. PMID: 31487757 [PubMed - as supplied by publisher]
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
Conclusions: Our findings indicate that ERVK expression and activity in SBMA is an unrecognized biomarker and facet of the disease. We discuss how our current understanding of ERVK-driven pathology may tie into key aspects of multi-system dysfunction in SBMA, with a focus on inflammation, proteinopathy, as well as DNA damage and repair.
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Publication date: Available online 29 August 2019Source: Integrative Medicine ResearchAuthor(s): Mudan Cai, Eun Jin YangAbstractAmyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterized by selective motor neuron cell death in the motor cortex, brainstem, and spinal cord. Two drugs for ALS, riluzole and edaravone, have been approved by FDA for the treatment of ALS patients. However, they have many side effects, and riluzole extends the patient’s life by only 2–3 months. Therefore, ALS patients seek an effective therapy for treating the symptoms or delaying the progression of A...
Source: Integrative Medicine Research - Category: Complementary Medicine Source Type: research
The primary role of magnetic resonance imaging (MRI) in routine diagnostic work-up of motor neuron disease patients is currently still largely limited to exclusion of relevant non-degenerative pathologies. We here present an illustrative case of a 63-year-old woman with early stage Frontotemporal-Dementia-Amyotrophic-Lateral-Sclerosis (FTD-ALS) spectrum disorder showing a striking hypointense signal of the cortical band along the precentral gyrus, termed “Motor Band Sign” (MBS). Based on this finding, we analysed the frequency of the MBS in clinical routine MRIs in a large consecutive series of ALS patients (MR...
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Source Type: research
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