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Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis.
Mol Brain. 2015 Oct 24; 8(1):67.MB

Abstract

BACKGROUND

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, which leads to the loss of upper and lower motor neurons, with a currently unknown etiology. Specific biomarkers could help in early detection and diagnosis, and could also act as indicators of disease progression and therapy effectiveness. MicroRNAs (miRNAs) are small (18-25 nucleotides), single-stranded non-coding RNA molecules that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression, and are essential for nervous system development. Many of the genes associated with genetic ALS have pathological biological pathways related to RNA metabolism, and their pathogenesis may be affecting the maturing processes of miRNA.

RESULTS

We compared miRNA from the plasma of sALS patients and healthy controls using two cohorts; a discovery cohort analyzed with microarray (16 sALS patients and ten healthy controls) and a validation cohort confirmed with qPCR (48 sALS patients, 47 healthy controls and 30 disease controls). We measured the total amount of extracted RNA along with a spike-in control that ensured the quality of our quantification. A percentage of the 10-40 nt RNAs extracted from the total RNA showed a significant increase in ALS patients. There was a negative correlation between total RNA concentration and disease duration from onset to end point. Three of the miRNAs were up-regulated and six were down-regulated significantly in the discovery cohort. Since an internal control is required as a sample stability indicator of both the patients and controls in microarray analysis, we selected the miRNA showing the smallest dispersion and equivalency between the two groups' mean value, and decided to use hsa-miR-4516. We found hsa-miR-4649-5p to be up-regulated, and hsa-miR-4299 to be down-regulated, where each was not influenced by clinical characteristics. EPHA4, a target gene linked to the nervous system which has also been reported to be a disease modifier of ALS, is the common and most notable target gene of hsa-miR-4649-5p and hsa-miR-4299.

CONCLUSION

We have shown the relationship circulating plasma miRNA has with both healthy controls and diseased patients. Hsa-miR-4649-5p and hsa-miR-4299 have the potential to be ALS diagnosis biomarkers.

Links

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Authors+Show Affiliations

Takahashi I
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. ikukotak@med.hokudai.ac.jp.
Hama Y
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. hama@pop.med.hokudai.ac.jp.
Matsushima M
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. mmasaaki@huhp.hokudai.ac.jp.
Hirotani M
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. hirotani@med.hokudai.ac.jp.
Kano T
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. tkanoh76@med.hokudai.ac.jp.
Hohzen H
Department of Neurology, Obihiro Kosei General Hospital, West 6, South 8, Obihiro, Hokkaido, 080-0016, Japan. hohzen@f1.octv.ne.jp.
Yabe I
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. yabe@med.hokudai.ac.jp.
Utsumi J
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. jutsumi@pop.med.hokudai.ac.jp. Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, 135-8550, Japan. jutsumi@pop.med.hokudai.ac.jp.
Sasaki H
Department of Neurology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. h-isasak@med.hokudai.ac.jp.

MeSH

AgedAmyotrophic Lateral SclerosisBiomarkersCase-Control StudiesCohort StudiesDown-RegulationFemaleGene Expression ProfilingHumansMaleMicroRNAsMiddle AgedOligonucleotide Array Sequence AnalysisParkinson DiseaseReal-Time Polymerase Chain ReactionReproducibility of ResultsTime FactorsUp-Regulation

Pub Type(s)

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

Language

eng

PubMed ID

26497046

Citation

Takahashi, Ikuko, et al. "Identification of Plasma microRNAs as a Biomarker of Sporadic Amyotrophic Lateral Sclerosis." Molecular Brain, vol. 8, no. 1, 2015, p. 67.
Takahashi I, Hama Y, Matsushima M, et al. Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. Mol Brain. 2015;8(1):67.
Takahashi, I., Hama, Y., Matsushima, M., Hirotani, M., Kano, T., Hohzen, H., Yabe, I., Utsumi, J., & Sasaki, H. (2015). Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. Molecular Brain, 8(1), 67. https://doi.org/10.1186/s13041-015-0161-7
Takahashi I, et al. Identification of Plasma microRNAs as a Biomarker of Sporadic Amyotrophic Lateral Sclerosis. Mol Brain. 2015 Oct 24;8(1):67. PubMed PMID: 26497046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. AU - Takahashi,Ikuko, AU - Hama,Yuka, AU - Matsushima,Masaaki, AU - Hirotani,Makoto, AU - Kano,Takahiro, AU - Hohzen,Hideki, AU - Yabe,Ichiro, AU - Utsumi,Jun, AU - Sasaki,Hidenao, Y1 - 2015/10/24/ PY - 2015/09/03/received PY - 2015/10/19/accepted PY - 2015/10/27/entrez PY - 2015/10/27/pubmed PY - 2016/7/7/medline SP - 67 EP - 67 JF - Molecular brain JO - Mol Brain VL - 8 IS - 1 N2 - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, which leads to the loss of upper and lower motor neurons, with a currently unknown etiology. Specific biomarkers could help in early detection and diagnosis, and could also act as indicators of disease progression and therapy effectiveness. MicroRNAs (miRNAs) are small (18-25 nucleotides), single-stranded non-coding RNA molecules that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression, and are essential for nervous system development. Many of the genes associated with genetic ALS have pathological biological pathways related to RNA metabolism, and their pathogenesis may be affecting the maturing processes of miRNA. RESULTS: We compared miRNA from the plasma of sALS patients and healthy controls using two cohorts; a discovery cohort analyzed with microarray (16 sALS patients and ten healthy controls) and a validation cohort confirmed with qPCR (48 sALS patients, 47 healthy controls and 30 disease controls). We measured the total amount of extracted RNA along with a spike-in control that ensured the quality of our quantification. A percentage of the 10-40 nt RNAs extracted from the total RNA showed a significant increase in ALS patients. There was a negative correlation between total RNA concentration and disease duration from onset to end point. Three of the miRNAs were up-regulated and six were down-regulated significantly in the discovery cohort. Since an internal control is required as a sample stability indicator of both the patients and controls in microarray analysis, we selected the miRNA showing the smallest dispersion and equivalency between the two groups' mean value, and decided to use hsa-miR-4516. We found hsa-miR-4649-5p to be up-regulated, and hsa-miR-4299 to be down-regulated, where each was not influenced by clinical characteristics. EPHA4, a target gene linked to the nervous system which has also been reported to be a disease modifier of ALS, is the common and most notable target gene of hsa-miR-4649-5p and hsa-miR-4299. CONCLUSION: We have shown the relationship circulating plasma miRNA has with both healthy controls and diseased patients. Hsa-miR-4649-5p and hsa-miR-4299 have the potential to be ALS diagnosis biomarkers. SN - 1756-6606 UR - https://www.unboundmedicine.com/medline/citation/26497046/Identification_of_plasma_microRNAs_as_a_biomarker_of_sporadic_Amyotrophic_Lateral_Sclerosis_ DB - PRIME DP - Unbound Medicine ER -