| Autor: |
Weskamp K; Department of Neurology.; Neuroscience Graduate Program, and., Tank EM; Department of Neurology., Miguez R; Department of Neurology., McBride JP; Department of Neurology.; Cellular and Molecular Biology Program, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., Gómez NB; Department of Neurology.; Cellular and Molecular Biology Program, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA., White M; Department of Basic and Clinical Neuroscience and., Lin Z; Department of Basic and Clinical Neuroscience and., Gonzalez CM; Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom., Serio A; Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom., Sreedharan J; Department of Basic and Clinical Neuroscience and., Barmada SJ; Department of Neurology.; Neuroscience Graduate Program, and.; Cellular and Molecular Biology Program, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA. |
| Abstrakt: |
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. |
