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

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.

Matrin-3 dysfunction in myopathy and motor neuron degeneration

“…It should be noted that homozygous MATR3 mice were used in this study, whereas the MATR3 patients harbor autosomal dominant mutations, making it difficult to compare these mice with human patients. A more recent model utilized the CRISPR/Cas9 system to create transgene mice with S85C MATR3 knock-in (Kao et al, 2020). In this study, MATR3 was effectively expressed in the spinal cord and the brain, resulting in neuropathological and behavioral changes such as neuroinflammation in the spinal cord and cerebellum, muscle atrophy, motor impairment, neuromuscular junction defects, and Purkinje cell degeneration.…”

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

“…Overexpression of both WT or mutant MATR3 caused myotoxicity. Very recently, a MATR3 S85C germline knock-in mouse was also generated [395]. Two independent groups found that MATR3 expression in Drosophila results in shortened lifespan and motor deficits, with disease-associated mutants exhibiting increased toxicity over MATR3(WT) [396,397].…”

Matrin 3 in neuromuscular disease: physiology and pathophysiology

“…Multiple groups have attempted to model MATR3-related disease in mice. Homozygous knockout of murine Matr3 is perinatally lethal, indicating that MATR3 is necessary for viability ( 100 ). In a separate model, overexpression of human MATR3(WT) or MATR3(Phe115Cys) in skeletal muscle results in age-dependent muscle fiber degeneration with extensive vacuoles, internalized nuclei, and gross atrophy.…”

“…A Ser85Cys mutation knockin model has also provided important pathogenic insights in the context of physiological MATR3 dosage ( 100 ). Homozygous knockin mice display age-dependent motor impairment, muscle denervation and pathology, and neuroinflammation.…”