MATR3 F115C knock-in mice do not exhibit motor defects or neuropathological features of ALS

Bruggen, Rebekah van; Maksimovic, Katarina; You, Justin; Tran, David; Lee, Hyeok Jun; Khan, Mashiat; Kao, Ching Serena; Kim, Jihye Rachel; Cho, Woo In; Chen, Xiao Xiao; Park, Jeehye

doi:10.1016/j.bbrc.2021.06.052

Cited by 9 publications

(11 citation statements)

References 33 publications

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“…This affect was most notable for MATR3 S85C , and least severe for MATR3 P154S . MATR3 F115C puncta showed no significant difference in circularity ratio as compared to MATR3 WT , supporting recent studies suggesting that this mutation does not significantly perturb MATR3 and, therefore, it may not be a causative mutation in ALS/FTD ( van Bruggen et al., 2021 ). The rounded appearance of the MATR3 WT puncta suggests that these structures may be dynamic liquid-like condensates.…”

Section: Resultssupporting

confidence: 80%

“…The FoldIndex algorithm ( Prilusky et al., 2005 ), which analyzes hydrophobicity and net charge per residue, predicts that most regions outside of these annotated domains are unfolded ( Figure 1 B). Fourteen different pathogenic mutations have been identified in MATR3, including S85C, F115C, P154S, and T622A, each of which are implicated in familial ALS/FTD, although it remains controversial if the F115C mutation drives ALS/FTD ( Johnson et al., 2014 ; Leblond et al., 2016 ; Lin et al., 2015 ; Marangi et al., 2017 ; Origone et al., 2015 ; Senderek et al., 2009 ; van Bruggen et al., 2021 ; Xu et al., 2016 ). Most of these pathogenic mutations are found in the largely disordered regions of the protein, and clustered near the N-terminus and C-terminus ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…The role of MATR3 and its pathogenic mutations have recently been investigated in several model systems ( Gallego-Iradi et al., 2015 ; Kao et al., 2020 ; Malik et al., 2018 ; Mensch et al., 2018 ; Moloney et al., 2018 ; Ramesh et al., 2020 ; van Bruggen et al., 2021 ; Zhang et al., 2019 ). Homozygous knockout of MATR3 in mice is embryonic lethal, suggesting that MATR3 is essential for development ( Quintero-Rivera et al., 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of MATR3 WT , MATR3 S85C , or MATR3 F115C as well as knock-in of MATR3 S85C in mice results in motor and neuronal defects ( Kao et al., 2020 ; Moloney et al., 2018 ; Zhang et al., 2019 ). However, knock-in of MATR3 F115C did not lead to muscle or neuronal pathology in mice, suggesting that MATR3 F115C may not be a causative mutation in ALS/FTD ( van Bruggen et al., 2021 ). Expression of MATR3 WT in primary neurons and Drosophila is associated with increased risk of death or shortened lifespan, and disease-associated mutations to MATR3 subtly enhance this effect ( Malik et al., 2018 ; Ramesh et al., 2020 ; Zhao et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

et al. 2022

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

et al. 2022

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“…The cervical (C3–5), thoracic (T6–8), and lumbar regions (L3–5) were used for sectioning. Brains were embedded in paraffin as previously described [ 14 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis

You

Maksimovic

Lee

et al. 2022

Biology

Self Cite

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The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.

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Saccharomyces cerevisiae as a research tool for RNA‐mediated human disease

Gastelum,

Michael,

Bolger

2023

WIREs RNA

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The budding yeast, Saccharomyces cerevisiae, has been used for decades as a powerful genetic tool to study a broad spectrum of biological topics. With its ease of use, economic utility, well‐studied genome, and a highly conserved proteome across eukaryotes, it has become one of the most used model organisms. Due to these advantages, it has been used to study an array of complex human diseases. From broad, complex pathological conditions such as aging and neurodegenerative disease to newer uses such as SARS‐CoV‐2, yeast continues to offer new insights into how cellular processes are affected by disease and how affected pathways might be targeted in therapeutic settings. At the same time, the roles of RNA and RNA‐based processes have become increasingly prominent in the pathology of many of these same human diseases, and yeast has been utilized to investigate these mechanisms, from aberrant RNA‐binding proteins in amyotrophic lateral sclerosis to translation regulation in cancer. Here we review some of the important insights that yeast models have yielded into the molecular pathology of complex, RNA‐based human diseases.This article is categorized under: RNA in Disease and Development > RNA in Disease

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MATR3 F115C knock-in mice do not exhibit motor defects or neuropathological features of ALS

Cited by 9 publications

References 33 publications

Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis

Saccharomyces cerevisiae as a research tool for RNA‐mediated human disease

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