Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Abstract The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43 A315T , with controlled neuronal over-expression. Constitutive expression of human TDP-43 A315T resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43 A315T brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43 A315T expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43 A315T mice are at least in part a direct and transient ...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
Publication date: Available online 11 October 2019Source: Neurophysiologie CliniqueAuthor(s): Chaojun Zheng, Yu Zhu, Minghao Shao, Dongqing Zhu, Hong Hu, Kai Qiao, Jianyuan JiangSummaryObjectivesTo investigate and compare split-hand phenomenon quantified by motor unit number index (MUNIX) between patients with cervical spondylotic amyotrophy (CSA) and those with amyotrophic lateral sclerosis (ALS).MethodsMUNIX was performed on abductor pollicis brevis (APB), abductor digiti minimi (ADM) and first dorsal interosseous (FDI) in 46 CSA patients, 39 ALS patients and 41 healthy subjects. Split-hand measurements including split-h...
Source: Neurophysiologie Clinique - Category: Neuroscience Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
The angiogenin (ANG) gene is mutated frequently in individuals with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Delivering human ANG to mice that display ALS-like symptoms extends their lifespan and improves motor function. ANG is a secretory vertebrate RNase that enters neuronal cells and cleaves a subset of tRNAs, leading to the inhibition of translation initiation and the assembly of stress granules. Here, using murine neuronal and astrocytic cell lines, we find that ANG triggers the activation of the Nrf2 (nuclear factor erythroid 2-rela...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Neurobiology Source Type: research
Nature Reviews Neurology, Published online: 11 October 2019; doi:10.1038/s41582-019-0276-zUltrasound success removes barriers to targeted drug delivery in amyotrophic lateral sclerosis
Source: Nature Reviews Neurology - Category: Neurology Authors: Source Type: research
ConclusionsIn this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Source Type: research
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
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