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Novel miR-b2122 regulates several ALS-related RNA-binding proteins.
Mol Brain. 2017 Oct 02; 10(1):46.MB

Abstract

Common pathological features of amyotrophic lateral sclerosis (ALS) include cytoplasmic aggregation of several RNA-binding proteins. Out of these RNA-binding proteins, TDP-43, FUS/TLS and RGNEF have been shown to co-aggregate with one another within motor neurons of sporadic ALS (sALS) patients, suggesting that there may be a common regulatory network disrupted. MiRNAs have been a recent focus in ALS research as they have been identified to be globally down-regulated in the spinal cord of ALS patients. The objective of this study was to identify if there are miRNA(s) dysregulated in sALS that are responsible for regulating the TDP-43, FUS/TLS and RGNEF network. In this study, we identify miR-194 and miR-b2122 to be significantly down-regulated in sALS patients, and were predicted to regulate TARDBP, FUS/TLS and RGNEF expression. Reporter gene assays and RT-qPCR revealed that miR-b2122 down-regulates the reporter gene through direct interactions with either the TARDBP, FUS/TLS, or RGNEF 3'UTR, while miR-194 down-regulates firefly expression when it contained either the TARDBP or FUS/TLS 3'UTR. Further, we showed that miR-b2122 regulates endogenous expression of all three of these genes in a neuronal-derived cell line. Also, an ALS-associated mutation in the FUS/TLS 3'UTR ablates the ability of miR-b2122 to regulate reporter gene linked to FUS/TLS 3'UTR, and sALS samples which showed a down-regulation in miR-b2122 also showed an increase in FUS/TLS protein expression. Overall, we have identified a novel miRNA that is down-regulated in sALS that appears to be a central regulator of disease-related RNA-binding proteins, and thus its dysregulation likely contributes to TDP-43, FUS/TLS and RGNEF pathogenesis in sALS.

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Authors+Show Affiliations

Hawley ZCE
Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. zhawley@uwo.ca.
Campos-Melo D
Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Strong MJ
Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Department of Pathology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Rm C7-120 LHSC, University Hospital, 339 Windermere Road, London, Ontario, N6A 5A5, Canada.

MeSH

3' Untranslated RegionsAmyotrophic Lateral SclerosisBase SequenceCell LineDown-RegulationHumansLuciferasesMicroRNAsMutationRNA, MessengerRNA-Binding ProteinsSpinal Cord

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28969660

Citation

Hawley, Zachary C E., et al. "Novel miR-b2122 Regulates Several ALS-related RNA-binding Proteins." Molecular Brain, vol. 10, no. 1, 2017, p. 46.
Hawley ZCE, Campos-Melo D, Strong MJ. Novel miR-b2122 regulates several ALS-related RNA-binding proteins. Mol Brain. 2017;10(1):46.
Hawley, Z. C. E., Campos-Melo, D., & Strong, M. J. (2017). Novel miR-b2122 regulates several ALS-related RNA-binding proteins. Molecular Brain, 10(1), 46. https://doi.org/10.1186/s13041-017-0326-7
Hawley ZCE, Campos-Melo D, Strong MJ. Novel miR-b2122 Regulates Several ALS-related RNA-binding Proteins. Mol Brain. 2017 Oct 2;10(1):46. PubMed PMID: 28969660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel miR-b2122 regulates several ALS-related RNA-binding proteins. AU - Hawley,Zachary C E, AU - Campos-Melo,Danae, AU - Strong,Michael J, Y1 - 2017/10/02/ PY - 2017/8/8/received PY - 2017/9/14/accepted PY - 2017/10/4/entrez PY - 2017/10/4/pubmed PY - 2018/7/24/medline KW - Amyotrophic lateral sclerosis (ALS) KW - FUS/TLS KW - MotomiRs KW - Motor neuron KW - Neurodegeneration KW - RGNEF KW - TDP-43 KW - mRNA stability KW - miRNAs SP - 46 EP - 46 JF - Molecular brain JO - Mol Brain VL - 10 IS - 1 N2 - Common pathological features of amyotrophic lateral sclerosis (ALS) include cytoplasmic aggregation of several RNA-binding proteins. Out of these RNA-binding proteins, TDP-43, FUS/TLS and RGNEF have been shown to co-aggregate with one another within motor neurons of sporadic ALS (sALS) patients, suggesting that there may be a common regulatory network disrupted. MiRNAs have been a recent focus in ALS research as they have been identified to be globally down-regulated in the spinal cord of ALS patients. The objective of this study was to identify if there are miRNA(s) dysregulated in sALS that are responsible for regulating the TDP-43, FUS/TLS and RGNEF network. In this study, we identify miR-194 and miR-b2122 to be significantly down-regulated in sALS patients, and were predicted to regulate TARDBP, FUS/TLS and RGNEF expression. Reporter gene assays and RT-qPCR revealed that miR-b2122 down-regulates the reporter gene through direct interactions with either the TARDBP, FUS/TLS, or RGNEF 3'UTR, while miR-194 down-regulates firefly expression when it contained either the TARDBP or FUS/TLS 3'UTR. Further, we showed that miR-b2122 regulates endogenous expression of all three of these genes in a neuronal-derived cell line. Also, an ALS-associated mutation in the FUS/TLS 3'UTR ablates the ability of miR-b2122 to regulate reporter gene linked to FUS/TLS 3'UTR, and sALS samples which showed a down-regulation in miR-b2122 also showed an increase in FUS/TLS protein expression. Overall, we have identified a novel miRNA that is down-regulated in sALS that appears to be a central regulator of disease-related RNA-binding proteins, and thus its dysregulation likely contributes to TDP-43, FUS/TLS and RGNEF pathogenesis in sALS. SN - 1756-6606 UR - https://www.unboundmedicine.com/medline/citation/28969660/Novel_miR_b2122_regulates_several_ALS_related_RNA_binding_proteins_ DB - PRIME DP - Unbound Medicine ER -