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Neuronal hyperexcitability drives TDP43 pathology by upregulating shortened TDP43 protein isoforms

Kaitlin Weskamp, Elizabeth M. Tank, Roberto Miguez, Nicolás B. Gómez, Matthew White, Zigiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, Sami J. Barmada
doi: https://doi.org/10.1101/648477
Kaitlin Weskamp
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA
2Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
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Elizabeth M. Tank
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA
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Roberto Miguez
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA
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Nicolás B. Gómez
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA
3Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA
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Matthew White
4Department of Basic and Clinical Neuroscience, King’s College London, London, UK
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Zigiang Lin
4Department of Basic and Clinical Neuroscience, King’s College London, London, UK
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Carmen Moreno Gonzalez
5Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK.
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Andrea Serio
5Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK.
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Jemeen Sreedharan
4Department of Basic and Clinical Neuroscience, King’s College London, London, UK
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Sami J. Barmada
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA
2Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
3Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA
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  • For correspondence: sbarmada@umich.edu
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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 show that hyperexcitability recapitulates TDP43 pathology by upregulating shortened (s) TDP43 splice isoforms. These truncated isoforms accumulate in the cytosol, where they form insoluble inclusions that sequester full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression is toxic to mammalian neurons, suggesting that neurodegeneration results from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts are enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. These studies uncover a hitherto unknown role of alternative TDP43 isoforms in ALS, and indicate that sTDP43 production may be a key contributor to the susceptibility of motor neurons in ALS.

TDP43, ALS, hyperexcitability, alternative splicing, TDP43 pathology, iPSC, iNeuron

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Posted May 24, 2019.
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Neuronal hyperexcitability drives TDP43 pathology by upregulating shortened TDP43 protein isoforms
Kaitlin Weskamp, Elizabeth M. Tank, Roberto Miguez, Nicolás B. Gómez, Matthew White, Zigiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, Sami J. Barmada
bioRxiv 648477; doi: https://doi.org/10.1101/648477
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Neuronal hyperexcitability drives TDP43 pathology by upregulating shortened TDP43 protein isoforms
Kaitlin Weskamp, Elizabeth M. Tank, Roberto Miguez, Nicolás B. Gómez, Matthew White, Zigiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, Sami J. Barmada
bioRxiv 648477; doi: https://doi.org/10.1101/648477

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