A mutant MATR3 mouse model to explain multisystem proteinopathy.
Amyotrophic Lateral Sclerosis
/ genetics
Animals
Dependovirus
/ genetics
Disease Models, Animal
Distal Myopathies
/ genetics
Gait Analysis
Gene Transfer Techniques
Genetic Predisposition to Disease
Humans
Laryngeal Diseases
/ genetics
Mice, Inbred C57BL
Mice, Transgenic
Microtubule-Associated Proteins
/ metabolism
Motor Activity
Muscle, Skeletal
/ metabolism
Mutation
Nuclear Matrix-Associated Proteins
/ genetics
Pharyngeal Diseases
/ genetics
RNA-Binding Proteins
/ genetics
Rotarod Performance Test
Sequestosome-1 Protein
/ metabolism
Spinal Cord
/ metabolism
Weight Loss
Matrin 3
adeno-associated virus
amyotrophic lateral sclerosis
multisystem proteinopathy
transgenic mice
vocal cord and pharyngeal weakness with distal myopathy
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
12
11
2018
revised:
08
04
2019
accepted:
28
04
2019
pubmed:
6
5
2019
medline:
14
4
2020
entrez:
7
5
2019
Statut:
ppublish
Résumé
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.
Substances chimiques
MATR3 protein, human
0
Map1lc3b protein, mouse
0
Microtubule-Associated Proteins
0
Nuclear Matrix-Associated Proteins
0
RNA-Binding Proteins
0
Sequestosome-1 Protein
0
Sqstm1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
182-192Informations de copyright
© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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