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Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

ABSTRACT: Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

SUBMITTER: Reichenstein I

PROVIDER: S-EPMC7057809 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

Reichenstein Irit I Eitan Chen C Diaz-Garcia Sandra S Haim Guy G Magen Iddo I Siany Aviad A Hoye Mariah L ML Rivkin Natali N Olender Tsviya T Toth Beata B Ravid Revital R Mandelbaum Amitai D AD Yanowski Eran E Liang Jing J Rymer Jeffrey K JK Levy Rivka R Beck Gilad G Ainbinder Elena E Farhan Sali M K SMK Lennox Kimberly A KA Bode Nicole M NM Behlke Mark A MA Möller Thomas T Saxena Smita S Moreno Cristiane A M CAM Costaguta Giancarlo G van Eijk Kristel R KR Phatnani Hemali H Al-Chalabi Ammar A Başak A Nazli AN van den Berg Leonard H LH Hardiman Orla O Landers John E JE Mora Jesus S JS Morrison Karen E KE Shaw Pamela J PJ Veldink Jan H JH Pfaff Samuel L SL Yizhar Ofer O Gross Christina C Brown Robert H RH Ravits John M JM Harms Matthew B MB Miller Timothy M TM Hornstein Eran E

Science translational medicine 20191201 523

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel <i>Kv10. ...[more]

PMID: 31852800

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Project description:Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.

Dataset Information

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

Publications

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

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