RETRACTED ARTICLE: Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons. Mutations in the gene encoding the nuclear matrix protein Matrin 3 have been found in familial cases of ALS, as well as autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We previously found that spinal cord and muscle, organs involved in either ALS or distal myopathy, have relatively lower levels of Matrin 3 compared to the brain and other peripheral organs in the murine system. This suggests that these organs may be vulnerable to any changes in Matrin 3. In order to determine the role of Matrin 3 in these diseases, we created a transgenic mouse model for human wild-type Matrin 3 using the mouse prion promoter (MoPrP) on a FVB background.We identified three founder transgenic lines that produced offspring in which mice developed either hindlimb paresis or paralysis with hindlimb and forelimb muscle atrophy. Muscles of affected mice showed a striking increase in nuclear Matrin 3, as well as the presence of rounded fibers, vacuoles, nuclear chains, and subsarcolemmal nuclei. Immunoblot analysis of the gastrocnemius muscle from phenotypic mice showed increased levels of Matrin 3 products migrating at approximately 120 (doublet), 90, 70, and 55 kDa. While there was no significant change in the levels of Matrin 3 in the spinal cord in the phenotypic mice, the ventral horn contained individual cells with cytoplasmic redistribution of Matrin 3, as well as gliosis. The phenotypes of these mice indicate that dysregulation of Matrin 3 levels is deleterious to neuromuscular function.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0393-5) contains supplementary material, which is available to authorized users.

The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins

“… 30 , 31 , 32 Recently, mice over-expressing human matrin-3 were reported to develop muscular atrophy and altered spinal cord distribution of matrin-3 protein. 54 Consistent with previous reports 30 , 31 , 32 on human matrinopathy, we observed both cytoplasmic and nuclear matrin-3 accumulation in E102Q-SigR1 over-expressing cells, along with the aggregation of other RBPs relevant to ALS (TDP-43 and FUS). Furthermore, matrin-3 mis-localization was induced by misfolded protein stress and impairment of degradation pathways in mSigR1 expressing cells ( Supplementary Figure 5C ).…”

Matrin3 binds directly to intronic pyrimidine‐rich sequences and controls alternative splicing

“…However, Matrin3 is found to be redistributed in the cytoplasm in some neurons of the spinal cord in transgenic mice over‐expressing wild‐type Matrin3, which exhibit muscle atrophy and weakness (Moloney et al . ). Therefore, although it still remains unknown whether either loss of function or gain of function is the main cause of these diseases, identification of the target RNAs and the function of Matrin3 could be the first step to elucidate the disease mechanism.…”

Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications

“…14 Transgenic mice overexpressing human MATR3 protein develop hindlimb paralysis and muscle atrophy, indicating that neuromuscular function is sensitive to MATR3 levels. 15 The protein forms a complex with two other ALS-associated RNA-binding proteins, TDP43 8 and FUS, 16,17 in a RNA-dependent manner and the p.S85C mutation enhances this interaction. 8 Thus, overlap might occur in the upstream regulatory proteins or downstream effector targets among ALS-RNA binding proteins.…”