Cytoplasmic TDP43 Binds microRNAs: New Disease Targets in Amyotrophic Lateral Sclerosis.

Autor:	Paez-Colasante X; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Figueroa-Romero C; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Rumora AE; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Hur J; Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States., Mendelson FE; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Hayes JM; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Backus C; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Taubman GF; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Heinicke L; Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI, United States., Walter NG; Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI, United States., Barmada SJ; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Sakowski SA; Department of Neurology, University of Michigan, Ann Arbor, MI, United States., Feldman EL; Department of Neurology, University of Michigan, Ann Arbor, MI, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular neuroscience [Front Cell Neurosci] 2020 May 12; Vol. 14, pp. 117. Date of Electronic Publication: 2020 May 12 (Print Publication: 2020).
DOI:	10.3389/fncel.2020.00117
Abstrakt:	Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and incurable neurodegenerative disease. Recent studies suggest that dysregulation of gene expression by microRNAs (miRNAs) may play an important role in ALS pathogenesis. The reversible nature of this dysregulation makes miRNAs attractive pharmacological targets and a potential therapeutic avenue. Under physiological conditions, miRNA biogenesis, which begins in the nucleus and includes further maturation in the cytoplasm, involves trans-activation response element DNA/RNA-binding protein of 43 kDa (TDP43). However, TDP43 mutations or stress trigger TDP43 mislocalization and inclusion formation, a hallmark of most ALS cases, that may lead to aberrant protein/miRNA interactions in the cytoplasm. Herein, we demonstrated that TDP43 exhibits differential binding affinity for select miRNAs, which prompted us to profile miRNAs that preferentially bind cytoplasmic TDP43. Using cellular models expressing TDP43 variants and miRNA profiling analyses, we identified differential levels of 65 cytoplasmic TDP43-associated miRNAs. Of these, approximately 30% exhibited levels that differed by more than 3-fold in the cytoplasmic TDP43 models relative to our control model. The hits included both novel miRNAs and miRNAs previously associated with ALS that potentially regulate several predicted genes and pathways that may be important for pathogenesis. Accordingly, these findings highlight specific miRNAs that may shed light on relevant disease pathways and could represent potential biomarkers and reversible treatment targets for ALS. (Copyright © 2020 Paez-Colasante, Figueroa-Romero, Rumora, Hur, Mendelson, Hayes, Backus, Taubman, Heinicke, Walter, Barmada, Sakowski and Feldman.)
Databáze:	MEDLINE
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