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

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Kaitlin Weskamp, Elizabeth M Tank, Roberto Miguez, Jonathon P McBride, Nicolás B Gómez, Matthew White, Ziqiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, Sami J Barmada

Original languageEnglish
Pages (from-to)1139-1155
Number of pages17
JournalJournal of Clinical Investigation
Volume130
Issue number3
Early online date12 Nov 2019
DOIs
Accepted/In press6 Nov 2019
E-pub ahead of print12 Nov 2019
Published2 Mar 2020

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Abstract

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.

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