MotomiRs: miRNAs in Motor Neuron Function and Disease

Hawley, Zachary C. E.; Campos-Melo, Danae; Droppelmann, Cristian A.; Strong, Michael J.

doi:10.3389/fnmol.2017.00127

Cited by 28 publications

(24 citation statements)

References 225 publications

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“…Loss of DICER function within progenitor cells results in aberrant motor neuron development while its loss in motor neuron leads to progressive motor neuron degeneration (Haramati et al, 2010; Chen and Wichterle, 2012). Furthermore, miRNAs are important players for NMJ function, synaptic plasticity and for maintaining cytoskeletal integrity (see review, Hawley et al, 2017).…”

Section: Dysregulation Of Microrna (Mirna) In Alsmentioning

confidence: 99%

RNA Dysregulation in Amyotrophic Lateral Sclerosis

2019

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Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease and is characterized by the degeneration of upper and lower motor neurons. It has become increasingly clear that RNA dysregulation is a key contributor to ALS pathogenesis. The major ALS genes SOD1, TARDBP, FUS, and C9orf72 are involved in aspects of RNA metabolism processes such as mRNA transcription, alternative splicing, RNA transport, mRNA stabilization, and miRNA biogenesis. In this review, we highlight the current understanding of RNA dysregulation in ALS pathogenesis involving these major ALS genes and discuss the potential of therapeutic strategies targeting disease RNAs for treating ALS.

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Section: Dysregulation Of Microrna (Mirna) In Alsmentioning

confidence: 99%

RNA Dysregulation in Amyotrophic Lateral Sclerosis

2019

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“…Alterations in RNA metabolism and microRNAs (miRs) can contribute to, and also be part of, mechanisms that initiate the disease ( Lemmens et al, 2010 ; Emde and Hornstein, 2014 ). miRs are post-transcriptional regulators that play an important role in many cellular processes, such as axon growth and retraction, and were demonstrated to be involved in many diseases, including neurodegenerative diseases, such as ALS ( Hawley et al, 2017 ; Molasy et al, 2017 ). Alterations in miR expression profile were identified specifically in axons of ALS models ( Rotem et al, 2017 ), as well in muscles leading to increasing attempts to either use or target miRs as therapeutic strategies ( Di Pietro et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

et al. 2018

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Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non–cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non–cell-autonomous mechanism of motor neuron degeneration in ALS.SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo.

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“…From this group of miRNAs that regulate NEFM and NEFH mRNA levels, only miR-9 has been reported to have a role in neuronal function. More specifically, by regulating several targets including OC1, FoxP1, MAP1B, and MCPIP1, miR-9 is critical for motor neuron development, function and survival [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs

2018

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Neurofilaments (NFs) are the most abundant cytoskeletal component of vertebrate myelinated axons. NFs function by determining axonal caliber, promoting axonal growth and forming a 3-dimensional lattice that supports the organization of cytoplasmic organelles. The stoichiometry of NF protein subunits (NFL, NFM and NFH) has to be tightly controlled to avoid the formation of NF neuronal cytoplasmic inclusions (NCIs), axonal degeneration and neuronal death, all pathological hallmarks of amyotrophic lateral sclerosis (ALS). The post-transcriptional control of NF transcripts is critical for regulating normal levels of NF proteins. Previously, we showed that miRNAs that are dysregulated in ALS spinal cord regulate the levels of NEFL mRNA. In order to complete the understanding of altered NF expression in ALS, in this study we have investigated the regulation of NEFM and NEFH mRNA levels by miRNAs. We observed that a small group of ALS-linked miRNAs that are expressed in human spinal motor neurons directly regulate NEFM and NEFH transcript levels in a manner that is associated with an increase in NFM and NFH protein levels in ALS spinal cord homogenates. In concert with previous observations demonstrating the suppression of NEFL mRNA steady state levels in ALS, these observations provide support for the hypothesis that the dysregulation of miRNAs in spinal motor neurons in ALS fundamentally alters the stoichiometry of NF expression, leading to the formation of pathological NCIs.

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MotomiRs: miRNAs in Motor Neuron Function and Disease

Cited by 28 publications

References 225 publications

RNA Dysregulation in Amyotrophic Lateral Sclerosis

RNA Dysregulation in Amyotrophic Lateral Sclerosis

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non–Cell-Autonomous Mechanism in ALS

Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs

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