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The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis.
Mol Neurobiol. 2017 08; 54(6):4329-4342.MN

Abstract

Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, the main activatory subunit of cyclin-dependent kinase 5 (CDK5). The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer's disease (AD). CDK5R1 displays a large and highly evolutionarily conserved 3'-untranslated region (3'-UTR), a fact that has suggested a role for this region in the post-transcriptional control of CDK5R1 expression. Our group has recently demonstrated that two miRNAs, miR-103 and miR-107, regulate CDK5R1 expression and affect the levels of p35. MiR-103 and miR-107 belong to the miR-15/107 family, a group of evolutionarily conserved miRNAs highly expressed in human cerebral cortex. In this work, we tested the hypothesis that other members of this group of miRNAs, in addition to miR-103 and miR-107, were able to modulate CDK5R1 expression. We provide evidence that several miRNAs belonging to the miR-15/107 family regulate p35 levels. BACE1 expression levels were also found to be modulated by different members of this family. Furthermore, overexpression of these miRNAs led to reduced APP phosphorylation levels at the CDK5-specific Thr668 residue. We also show that miR-15/107 miRNAs display reduced expression levels in hippocampus and temporal cortex, but not in cerebellum, of AD brains. Moreover, increased CDK5R1 mRNA levels were observed in AD hippocampus tissues. Our results suggest that the downregulation of the miR-15/107 family might have a role in the pathogenesis of AD by increasing the levels of CDK5R1/p35 and consequently enhancing CDK5 activity.

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Authors+Show Affiliations

Moncini S
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
Lunghi M
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
Valmadre A
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
Grasso M
Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy.
Del Vescovo V
Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy.
Riva P
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
Denti MA
Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy. Istituto di Neuroscienze, CNR, Viale Giuseppe Colombo 3, 35121, Padova, Italy.
Venturin M
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy. marco.venturin@unimi.it.

MeSH

Alzheimer DiseaseAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesCase-Control StudiesCell Line, TumorCyclin-Dependent Kinase 5Gene Expression RegulationHEK293 CellsHippocampusHumansMicroRNAsNerve Tissue ProteinsRNA, MessengerTemporal Lobe

Pub Type(s)

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

Language

eng

PubMed ID

27343180

Citation

Moncini, Silvia, et al. "The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 With Implications for Alzheimer's Disease Pathogenesis." Molecular Neurobiology, vol. 54, no. 6, 2017, pp. 4329-4342.
Moncini S, Lunghi M, Valmadre A, et al. The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis. Mol Neurobiol. 2017;54(6):4329-4342.
Moncini, S., Lunghi, M., Valmadre, A., Grasso, M., Del Vescovo, V., Riva, P., Denti, M. A., & Venturin, M. (2017). The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis. Molecular Neurobiology, 54(6), 4329-4342. https://doi.org/10.1007/s12035-016-0002-4
Moncini S, et al. The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 With Implications for Alzheimer's Disease Pathogenesis. Mol Neurobiol. 2017;54(6):4329-4342. PubMed PMID: 27343180.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis. AU - Moncini,Silvia, AU - Lunghi,Marta, AU - Valmadre,Alice, AU - Grasso,Margherita, AU - Del Vescovo,Valerio, AU - Riva,Paola, AU - Denti,Michela Alessandra, AU - Venturin,Marco, Y1 - 2016/06/24/ PY - 2016/02/12/received PY - 2016/06/14/accepted PY - 2016/6/28/pubmed PY - 2018/5/11/medline PY - 2016/6/26/entrez KW - Alzheimer’s disease KW - CDK5 KW - CDK5R1/p35 KW - Post-transcriptional regulation KW - miR-15/107 SP - 4329 EP - 4342 JF - Molecular neurobiology JO - Mol Neurobiol VL - 54 IS - 6 N2 - Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, the main activatory subunit of cyclin-dependent kinase 5 (CDK5). The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer's disease (AD). CDK5R1 displays a large and highly evolutionarily conserved 3'-untranslated region (3'-UTR), a fact that has suggested a role for this region in the post-transcriptional control of CDK5R1 expression. Our group has recently demonstrated that two miRNAs, miR-103 and miR-107, regulate CDK5R1 expression and affect the levels of p35. MiR-103 and miR-107 belong to the miR-15/107 family, a group of evolutionarily conserved miRNAs highly expressed in human cerebral cortex. In this work, we tested the hypothesis that other members of this group of miRNAs, in addition to miR-103 and miR-107, were able to modulate CDK5R1 expression. We provide evidence that several miRNAs belonging to the miR-15/107 family regulate p35 levels. BACE1 expression levels were also found to be modulated by different members of this family. Furthermore, overexpression of these miRNAs led to reduced APP phosphorylation levels at the CDK5-specific Thr668 residue. We also show that miR-15/107 miRNAs display reduced expression levels in hippocampus and temporal cortex, but not in cerebellum, of AD brains. Moreover, increased CDK5R1 mRNA levels were observed in AD hippocampus tissues. Our results suggest that the downregulation of the miR-15/107 family might have a role in the pathogenesis of AD by increasing the levels of CDK5R1/p35 and consequently enhancing CDK5 activity. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/27343180/The_miR_15/107_Family_of_microRNA_Genes_Regulates_CDK5R1/p35_with_Implications_for_Alzheimer's_Disease_Pathogenesis_ DB - PRIME DP - Unbound Medicine ER -