A mutant MATR3 mouse model to explain multisystem proteinopathy

• Published in: The Journal of pathology Vol. 249; no. 2; pp. 182 - 192
• Main Authors: Zhang, Xiao, Yamashita, Satoshi, Hara, Kentaro, Doki, Tsukasa, Tawara, Nozomu, Ikeda, Tokunori, Misumi, Yohei, Zhang, Ziwei, Matsuo, Yoshimasa, Nagai, Makiko, Kurashige, Takashi, Maruyama, Hirofumi, Ando, Yukio
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2019; Wiley Subscription Services, Inc
• Subjects: Actin; adeno‐associated virus; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animal models; Animals; Astrocytes; Body weight; Chaperones; Dependovirus - genetics; Disease Models, Animal; Distal Myopathies - genetics; Distal Myopathies - metabolism; Distal Myopathies - pathology; Distal Myopathies - physiopathology; Gait Analysis; Gene Transfer Techniques; Genetic Predisposition to Disease; Histology; Humans; Laryngeal Diseases - genetics; Laryngeal Diseases - metabolism; Laryngeal Diseases - pathology; Laryngeal Diseases - physiopathology; Matrin 3; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microtubule-Associated Proteins - metabolism; Motor Activity; Motor neurons; multisystem proteinopathy; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscles; Mutation; Myopathy; Nuclear Matrix-Associated Proteins - genetics; Nuclear Matrix-Associated Proteins - metabolism; Pathogenesis; Pharyngeal Diseases - genetics; Pharyngeal Diseases - metabolism; Pharyngeal Diseases - pathology; Pharyngeal Diseases - physiopathology; Pharynx; Poultry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Rotarod Performance Test; Sequestosome-1 Protein - metabolism; Spinal cord; Spinal Cord - metabolism; Spinal Cord - pathology; Spinal Cord - physiopathology; Transgenic animals; Transgenic mice; Vacuoles; Viruses; vocal cord and pharyngeal weakness with distal myopathy; Weight Loss; vocal cord and pharyngeal weakness with distal myopathy; multisystem proteinopathy; Matrin 3; adeno-associated virus; transgenic mice; amyotrophic lateral sclerosis
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5289

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno‐associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken β‐actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3‐II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber‐size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.