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Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels.
Mol Brain. 2013 May 24; 6:26.MB

Abstract

BACKGROUND

Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. There is emerging evidence that alterations in RNA metabolism may be critical in the pathogenesis of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that are key determinants of mRNA stability. Considering that miRNAs are increasingly being recognized as having a role in a variety of neurodegenerative diseases, we decided to characterize the miRNA expression profile in spinal cord (SC) tissue in sporadic ALS (sALS) and controls. Furthermore, we performed functional analysis to identify a group of dysregulated miRNAs that could be responsible for the selective suppression of low molecular weight neurofilament (NFL) mRNA observed in ALS.

RESULTS

Using TaqMan arrays we analyzed 664 miRNAs and found that a large number of miRNAs are differentially expressed in ventral lumbar SC in sALS compared to controls. We observed that the majority of dysregulated miRNAs are down-regulated in sALS SC tissues. Ingenuity Pathway Analysis (IPA) showed that dysregulated miRNAs are linked with nervous system function and cell death. We used two prediction algorithms to develop a panel of miRNAs that have recognition elements within the human NFL mRNA 3'UTR, and then we performed functional analysis for these miRNAs. Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3'UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS.

CONCLUSIONS

The miRNA expression profile is broadly altered in the SC in sALS. Amongst these is a group of dysregulated miRNAs directly regulate the NFL mRNA 3'UTR, suggesting a role in the selective suppression of NFL mRNA in the ALS spinal motor neuron neurofilamentous aggregate formation.

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Authors+Show Affiliations

Campos-Melo D
Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Droppelmann CA
No affiliation info available
He Z
No affiliation info available
Volkening K
No affiliation info available
Strong MJ
No affiliation info available

MeSH

3' Untranslated RegionsAdultAgedAmyotrophic Lateral SclerosisBase SequenceCase-Control StudiesCell DeathDemographyFemaleGene Expression ProfilingGene Regulatory NetworksGenes, ReporterHEK293 CellsHumansLuciferasesMaleMicroRNAsMiddle AgedMolecular Sequence DataMutationNervous SystemNeurofilament ProteinsRNA, MessengerSequence AlignmentSpinal CordUp-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23705811

Citation

Campos-Melo, Danae, et al. "Altered microRNA Expression Profile in Amyotrophic Lateral Sclerosis: a Role in the Regulation of NFL mRNA Levels." Molecular Brain, vol. 6, 2013, p. 26.
Campos-Melo D, Droppelmann CA, He Z, et al. Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain. 2013;6:26.
Campos-Melo, D., Droppelmann, C. A., He, Z., Volkening, K., & Strong, M. J. (2013). Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Molecular Brain, 6, 26. https://doi.org/10.1186/1756-6606-6-26
Campos-Melo D, et al. Altered microRNA Expression Profile in Amyotrophic Lateral Sclerosis: a Role in the Regulation of NFL mRNA Levels. Mol Brain. 2013 May 24;6:26. PubMed PMID: 23705811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. AU - Campos-Melo,Danae, AU - Droppelmann,Cristian A, AU - He,Zhongping, AU - Volkening,Kathryn, AU - Strong,Michael J, Y1 - 2013/05/24/ PY - 2013/04/21/received PY - 2013/05/22/accepted PY - 2013/5/28/entrez PY - 2013/5/28/pubmed PY - 2013/12/16/medline SP - 26 EP - 26 JF - Molecular brain JO - Mol Brain VL - 6 N2 - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. There is emerging evidence that alterations in RNA metabolism may be critical in the pathogenesis of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that are key determinants of mRNA stability. Considering that miRNAs are increasingly being recognized as having a role in a variety of neurodegenerative diseases, we decided to characterize the miRNA expression profile in spinal cord (SC) tissue in sporadic ALS (sALS) and controls. Furthermore, we performed functional analysis to identify a group of dysregulated miRNAs that could be responsible for the selective suppression of low molecular weight neurofilament (NFL) mRNA observed in ALS. RESULTS: Using TaqMan arrays we analyzed 664 miRNAs and found that a large number of miRNAs are differentially expressed in ventral lumbar SC in sALS compared to controls. We observed that the majority of dysregulated miRNAs are down-regulated in sALS SC tissues. Ingenuity Pathway Analysis (IPA) showed that dysregulated miRNAs are linked with nervous system function and cell death. We used two prediction algorithms to develop a panel of miRNAs that have recognition elements within the human NFL mRNA 3'UTR, and then we performed functional analysis for these miRNAs. Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3'UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS. CONCLUSIONS: The miRNA expression profile is broadly altered in the SC in sALS. Amongst these is a group of dysregulated miRNAs directly regulate the NFL mRNA 3'UTR, suggesting a role in the selective suppression of NFL mRNA in the ALS spinal motor neuron neurofilamentous aggregate formation. SN - 1756-6606 UR - https://www.unboundmedicine.com/medline/citation/23705811/Altered_microRNA_expression_profile_in_Amyotrophic_Lateral_Sclerosis:_a_role_in_the_regulation_of_NFL_mRNA_levels_ L2 - https://molecularbrain.biomedcentral.com/articles/10.1186/1756-6606-6-26 DB - PRIME DP - Unbound Medicine ER -