A High-Throughput Screening Identifies MicroRNA Inhibitors That Influence Neuronal Maintenance and/or Response to Oxidative Stress
Pallarès-Albanell, Joan (Centre de Regulació Genòmica)
Zomeño-Abellán, M. Teresa (Centre de Regulació Genòmica)
Escaramís, Georgia (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Pantano, Lorena (Harvard T.H. Chan School of Public Health. Department of Biostatistics)
Soriano, Aroa (Hospital Universitari Vall d'Hebron)
Segura, Miguel F. (Hospital Universitari Vall d'Hebron)
Martí, Eulàlia (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Small non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36. 6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications.
Ajuts:	Ministerio de Economía y Competitividad SAF2014-60551-R Ministerio de Economía y Competitividad R-SAF2017-88452-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Mirnas ; Non-coding RNAs ; Neurodegeneration ; High-throughput screening ; Oxidative stress ; Mitochondrial function ; Expression profiles ; Small RNA sequencing
Publicat a:	Molecular Therapy. Nucleic Acids, Vol. 17 (june 2019) , p. 374-387, ISSN 2162-2531

DOI: 10.1016/j.omtn.2019.06.007
PMID: 31302497

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