Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death

Abstract The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATGMet85), denoted here as Met85-TDP-35. Met85-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met85-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met85-TDP-35 in primary motor neurons resulted in the formation of Met85-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met85-TDP-35 labeled the 35-kDa lower molecular weight species on immunoblots of urea-soluble extracts from ALS-FTLD disease-affected tissues and co-labeled TDP-43-positive inclusions in ALS spinal cord sections, confirming the physiological relevance of this species. These results show that the 35-kDa low molecular weight species in ALS-FTLD can be generated from an abnormal splicing event and use of a downstream initiation codon and may represent a mechanism by which TDP-43 elicits its pathogenicity.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Last month, House Speaker Nancy Pelosi unveiled aradical drug pricing plan, H.R. 3, that could jeopardize the development of innovative treatments for some of the most challenging diseases and leave U.S. patients behind. For example,researchers are focused every day on finding new treatments and cures for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig ’s Disease), but Pelosi’s plan could threaten future treatments for ALS by imposing government-set prices on critical medicines, creating increased uncertainty and eroding incentives for investment into risky research and development (R&D).
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Publication date: Available online 13 October 2019Source: NeuroImageAuthor(s): Aurélien Massire, Henitsoa Rasoanandrianina, Maxime Guye, Virginie CallotAbstractT1 mapping lacks specificity toward a single particular biological feature, however it has the potential to discriminate spinal cord regional tissue organization and characterize tissue microstructural impairments occurring in neurodegenerative pathologies. In this exploratory work, T1 mapping of the cervical spinal cord with a 300-μm in-plane resolution was performed on fourteen healthy subjects at 7 T, using the MP2RAGE sequence. Individual images from...
Source: NeuroImage - Category: Neuroscience Source Type: research
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
AbstractNeurodegenerative diseases are multifactorial debilitating disorders of the nervous system affecting approximately 30 million individuals worldwide. Mitochondrial dysfunction and oxidative stress have also been implicated in causing neurodegeneration. As life expectancy is increasing, neurodegenerative disorders are becoming a major social issue. None of the drugs currently available for treatment are capable of healing the patient. This means that new molecules should be explored. Plants have been used for treatment of countless medical conditions and extensive research is being carried out on species of the Myrta...
Source: Inflammopharmacology - Category: Drugs & Pharmacology Source Type: research
Conclusions This study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.
Source: Neurology Clinical Practice - Category: Neurology Authors: Tags: MRI, MRS, Amyotrophic lateral sclerosis Research Source Type: research
Ye Xu Successful cancer therapy requires drugs being precisely delivered to tumors. Nanosized drugs have attracted considerable recent attention, but their toxicity and high immunogenicity are important obstacles hampering their clinical translation. Here we report a novel “cocktail therapy” strategy based on excess natural killer cell-derived exosomes (NKEXOs) in combination with their biomimetic core–shell nanoparticles (NNs) for tumor-targeted therapy. The NNs were self- assembled with a dendrimer core loading therapeutic miRNA and a hydrophilic NKEXOs shell. Their successful fab...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article 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: Neurology Neuroimmunology and Neuroinflammation - Category: Neurology Authors: Tags: All Immunology, All Clinical Neurology, Amyotrophic lateral sclerosis, All Genetics Article Source Type: research
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Source: EMBO Journal - Category: Molecular Biology Authors: Tags: Neuroscience, RNA Biology Articles Source Type: research
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