Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

Ching Serena Kao, Rebekah Bruggen, Jihye Rachel Kim, Xiao Xiao Lily Chen, Cadia Chan, Jooyun Lee, Woo In Cho, Melody Zhao, Claudia Arndt, Katarina Maksimovic, Mashiat Khan, Qiumin Tan, Michael D. Wilson and Jeehye Park ()
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Ching Serena Kao: The Hospital for Sick Children
Rebekah Bruggen: The Hospital for Sick Children
Jihye Rachel Kim: The Hospital for Sick Children
Xiao Xiao Lily Chen: The Hospital for Sick Children
Cadia Chan: The Hospital for Sick Children
Jooyun Lee: The Hospital for Sick Children
Woo In Cho: The Hospital for Sick Children
Melody Zhao: The Hospital for Sick Children
Claudia Arndt: The Hospital for Sick Children
Katarina Maksimovic: The Hospital for Sick Children
Mashiat Khan: The Hospital for Sick Children
Qiumin Tan: University of Alberta
Michael D. Wilson: The Hospital for Sick Children
Jeehye Park: The Hospital for Sick Children

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

Date: 2020
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DOI: 10.1038/s41467-020-18949-w

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