Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
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Source: Toxicology - Category: Toxicology Authors: Tags: Toxicology Source Type: research
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Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
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Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
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Source: Journal of Applied Oral Science - Category: Dentistry Source Type: research
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Source: Innovations in Clinical Neuroscience - Category: Neuroscience Authors: Tags: Commentary Current Issue Source Type: research
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Source: Journal of the Neurological Sciences - Category: Neurology Authors: Source Type: research
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Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research
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Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research
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Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
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