Dysregulated mi RNA biogenesis downstream of cellular stress and ALS ‐causing mutations: a new mechanism for ALS

Abstract

Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNAbinding protein genes. Here, we show that extensive downregulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…Defects in miRNA biogenesis, for example via knockout of Dicer, has been correlated with decreased motor activity and survival, muscle atrophy, denervation, spinal cord sclerosis, and axonopathy in mice [113]. Additionally, previous studies have demonstrated decreased miRNA expression in the ventral lumbar spinal cord from patients with ALS [114], and also in spinal MN with ALS-causing mutations [115]. These results highlight the potential utility of miRNAs as biomarkers for ALS.…”

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

“…Moreover, misfolded proteins, such as ALS-linked variants of superoxide dismutase 1 (SOD1), can specifically accumulate and aggregate with SGs, which influences their composition and dynamics and triggers an aberrant liquid-tosolid transition (Mateju et al, 2017). Importantly, pathogenic ALScausing mutations in FUS are sufficient to inhibit miRNA biogenesis (Eitan and Hornstein, 2016;Emde et al, 2015).…”

“…Therefore, it is critical to understand how their expression is controlled -especially under stress conditions. miRNAs are prime candidates to control gene expression, as the miRNA expression profile is substantially changed in response to different stresses or diseases (Emde et al, 2015;Freiesleben et al, 2016;Lu et al, 2005;Marrone et al, 2012;Piwecka et al, 2015). This change in miRNA expression has a profound impact on the ability of the cell, or even the whole organism, to manage stress responses (Cicek et al, 2016;Edeleva and Shcherbata, 2013;Leung and Sharp, 2010;Mori et al, 2012).…”

“…Cellular stresses, such as reactive oxygen species (ROS), phorbol ester and Ras oncogene activation also inhibit Dicer protein expression in several cell types (Wiesen and Tomasi, 2009), and Dicer expression and activity is important for adaptive cellular responses to chronic hypoxic stress (Ho et al, 2012). In addition, upon stress, Dicer and Drosha can directly bind to the LCD proteins TAR DNA-binding protein 43 (TDP43; also known as TARDBP) and FUS in SGs, which affects the efficiency of their function in miRNA processing (Eitan and Hornstein, 2016;Emde et al, 2015;Kawahara and Mieda-Sato, 2012). These data demonstrate that Drosha and Dicer, key components that regulate the first steps of miRNA biogenesis, are controlled by stress, which in turn affects the cellular ability to cope with stress.…”

Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes

“…knocking down DICER1 abolished behavioral resilience to stress. Chronic stress up-regulates cellular oxidative stress, which is known to inhibit microRNA biogenesis by modulating DICER1 activity [58] and altered intracellular reactive oxygen species production has been proposed to be a cause of idiopathic male infertility [59]. Future studies are required to clarify the mechanisms involved.…”