The microRNA miR-375-3p and the Tumor Suppressor NDRG2 are Involved in Sporadic Amyotrophic Lateral Sclerosis

Rohm, Marlena; May, Caroline; Marcus, Katrin; Steinbach, Simone; Theis, Verena; Theiß, Carsten; Matschke, Veronika

doi:10.33594/000000099

Cited by 27 publications

(12 citation statements)

References 46 publications

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“…A very original contribution recently came from Freischmidt and colleagues [103] who identified, by proteomic and biochemical studies, the members of the fragile X protein [106], an RBP implicated in neural function and degeneration [107], and of proapoptotic targets such as p53. In concordance with this result, in the sALS wobbler mouse-a model displaying almost all clinical hallmarks of human ALS patients [108]-miRNA-375-3p downregulation resulted in inefficient p53 inhibition, increased production of reactive oxygen species, and induced apoptosis [109].…”

Section: Integrative Mirna-omics Studies In Alssupporting

confidence: 60%

“…Two deep mechanistic studies based on extensive RNA sequencing were performed by De Santis et al and by Capauto et al In human MNs derived from mutant FUS-induced pluripotent stem cells (iPSCs), De Santis and collaborators showed the decreased levels of the MN protective miRNA-375, leading to the upregulation of ELAVL4[106], an RBP implicated in neural function and degeneration[107], and of proapoptotic targets such as p53. In concordance with this result, in the sALS wobbler mouse-a model displaying almost all clinical hallmarks of human ALS patients[108]-miRNA-375-3p downregulation resulted in inefficient p53 inhibition, increased production of reactive oxygen species, and induced apoptosis[109].Instead, in the FUS mutant MNs differentiated from mouse embryonic stem cells (ESCs), Capauto and colleagues demonstrated the upregulation of miR-409-3p and miR-495-3p and concomitant downregulation of Gria2, a subunit of the AMPA receptor triggering a cascade of MN-damaging excitotoxic events (Figure2Eand[110]). With the same rationale, whole transcriptomics was performed in SC ventral horns of post mortem sALS human donors, revealing the downregulation of neuronal genes and the upregulation of glial ones[111].…”

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confidence: 57%

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RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective

Laneve

Tollis

Caffarelli

2021

IJMS

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RNA metabolism is central to cellular physiopathology. Almost all the molecular pathways underpinning biological processes are affected by the events governing the RNA life cycle, ranging from transcription to degradation. The deregulation of these processes contributes to the onset and progression of human diseases. In recent decades, considerable efforts have been devoted to the characterization of noncoding RNAs (ncRNAs) and to the study of their role in the homeostasis of the nervous system (NS), where they are highly enriched. Acting as major regulators of gene expression, ncRNAs orchestrate all the steps of the differentiation programs, participate in the mechanisms underlying neural functions, and are crucially implicated in the development of neuronal pathologies, among which are neurodegenerative diseases. This review aims to explore the link between ncRNA dysregulation and amyotrophic lateral sclerosis (ALS), the most frequent motoneuron (MN) disorder in adults. Notably, defective RNA metabolism is known to be largely associated with this pathology, which is often regarded as an RNA disease. We also discuss the potential role that these transcripts may play as diagnostic biomarkers and therapeutic targets.

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Section: Integrative Mirna-omics Studies In Alssupporting

confidence: 60%

supporting

confidence: 57%

RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective

Laneve

Tollis

Caffarelli

2021

IJMS

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“…One of the primary objectives of this study was to determine whether disruption of scat expression in adult flies caused phenotypes like those observed in the wobbler mouse. While mutations in Vps54 have not been directly linked to human disease, the wobbler mouse has been used by many researchers as a model for the sporadic form of ALS because of striking similarities to ALS pathology ( Ikeda et al, 1998 ; Dennis and Citron, 2009 ; Nieto-Gonzalez et al, 2011 ; Moser et al, 2013 ; Dahlke et al, 2015 ; Schmitt-John, 2015 ; Klatt et al, 2019 ; Rohm et al, 2019 ; Cihankaya et al, 2021 ; De Nicola et al, 2021 ). It has previously been shown that scat mutants share spermatogenesis defects caused by Golgi dysfunction with the wobbler mouse ( Castrillon et al, 1993 ; Fari et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Vps54 Regulates Lifespan and Locomotor Behavior in Adult Drosophila melanogaster

2021

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Vps54 is an integral subunit of the Golgi-associated retrograde protein (GARP) complex, which is involved in tethering endosome-derived vesicles to the trans-Golgi network (TGN). A destabilizing missense mutation in Vps54 causes the age-progressive motor neuron (MN) degeneration, muscle weakness, and muscle atrophy observed in the wobbler mouse, an established animal model for human MN disease. It is currently unclear how the disruption of Vps54, and thereby the GARP complex, leads to MN and muscle phenotypes. To develop a new tool to address this question, we have created an analogous model in Drosophila by generating novel loss-of-function alleles of the fly Vps54 ortholog (scattered/scat). We find that null scat mutant adults are viable but have a significantly shortened lifespan. Like phenotypes observed in the wobbler mouse, we show that scat mutant adults are male sterile and have significantly reduced body size and muscle area. Moreover, we demonstrate that scat mutant adults have significant age-progressive defects in locomotor function. Interestingly, we see sexually dimorphic effects, with scat mutant adult females exhibiting significantly stronger phenotypes. Finally, we show that scat interacts genetically with rab11 in MNs to control age-progressive muscle atrophy in adults. Together, these data suggest that scat mutant flies share mutant phenotypes with the wobbler mouse and may serve as a new genetic model system to study the cellular and molecular mechanisms underlying MN disease.

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“…Due to the downregulation of miR-375-3p, the inhibition of p53 is ineffective, resulting in overexpression of NDRG2, increasing the generation of ROS and creating a vicious circle. Therefore, increased miR-375-3p might be a protective mechanism to prevent cell apoptosis by decreasing p53 expression and maintaining the NDRG2 level [83].…”

Section: Mirna and Neuronal Survival And Apoptosis In Alsmentioning

confidence: 99%

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis

Liu

Zhou

Guan

et al. 2022

Cells

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.

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The microRNA miR-375-3p and the Tumor Suppressor NDRG2 are Involved in Sporadic Amyotrophic Lateral Sclerosis

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 27 publications

References 46 publications

RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective

RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective

Vps54 Regulates Lifespan and Locomotor Behavior in Adult Drosophila melanogaster

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis

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