Matrin 3 Is a Component of Neuronal Cytoplasmic Inclusions of Motor Neurons in Sporadic Amyotrophic Lateral Sclerosis

Abstract

Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.

RNA processing in skeletal muscle biology and disease

“…TDP43 also plays a role in RNA stability and homeostasis [158], and whole genome RNA instability has been recently demonstrated in fibroblasts from individuals with ALS [159]. TDP43 interacts with other RNA processing factors, such as Matrin-3 (MATR3) and Fused-insarcoma (FUS) [160,161], that are frequently mutated in ALS [161][162][163][164]. While MATR3 is involved in polyadenylation site selection and intron retention via interactions with PABPN1 [162][163][164], FUS is a RBP that colocalizes with wild-type TDP43 in cytoplasmic inclusion bodies in models of ALS [161].…”

Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization

“…A total of 13 pathogenic MATR3 mutations have now been identified, most of which result in amino acid substitutions within disordered stretches of the MATR3 protein ( Figure 1A ) ( Millecamps et al, 2014 ; Lin et al, 2015a ; Origone et al, 2015 ; Leblond et al, 2016 ; Xu et al, 2016 ; Marangi et al, 2017 ). Additionally, post-mortem analyses demonstrated MATR3 pathology—consisting of cytoplasmic MATR3 accumulation as well as strong nuclear immunostaining—in patients with sporadic ALS and familial disease due to C9orf72 hexanucleotide expansions and FUS mutations ( Dreser et al, 2017 ; Tada et al, 2018 ). Together, these observations suggest that MATR3 may be a common mediator of disease even in those without MATR3 mutations.…”

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

“…This may be particularly relevant for families with sporadic cases of C9orf72 ALS/FTD. Ectopic cytoplasmic localization of mutant TDP43, FUS and MATR3 or overexpression of wildtype TDP43, FUS and MATR3 protein has been shown to be associated with ALS phenotypes in patients and model systems, respectively (Lagier-Tourenne, Polymenidou et al, 2010, Malik, Miguez et al, 2018, Mitchell, McGoldrick et al, 2013, Tada, Doi et al, 2018, Wils, Kleinberger et al, 2010. C9orf72, a DENN (differentially expressed in normal and neoplastic cells) domain containing protein, has been shown to play a role in autophagy and immune-regulatory functions (Lall & Baloh, 2017, Levine, Daniels et al, 2013, Nassif, Woehlbier et al, 2017.…”