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The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

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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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Acknowledgments

The authors would like to thank the MRC London Neurodegenerative Diseases Brain Bank, the Newcastle Brain Tissue Resource, and the South West Dementia Brain Bank (SWDBB) for providing brain tissue for this study. The SWDBB is supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly), Brains for Dementia Research and the Medical Research Council. This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (RBFR0895DC_02, FIRB (Basic Research Investment Fund) 2008 Grant to MV and RBFR0895DC_01, FIRB (Basic Research Investment Fund) 2008 Grant to MAD).

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy

    Silvia Moncini, Marta Lunghi, Alice Valmadre, Paola Riva & Marco Venturin

  2. Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy

    Margherita Grasso, Valerio Del Vescovo & Michela Alessandra Denti

  3. Istituto di Neuroscienze, CNR, Viale Giuseppe Colombo 3, 35121, Padova, Italy

    Michela Alessandra Denti

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  1. Silvia Moncini
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Correspondence to Marco Venturin.

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Table S1

Oligonucleotide pairs designed to generate wild-type and mutated miR-sensor constructs (XLSX 10 kb)

Fig. S1

Validation of miRNA sensors. a Luciferase activity of miRNA sensor constructs in SK-N-BE cells normalized on pmirGLO-empty vector. b Luciferase activity of representative miRNA sensors with a sequence perfectly complementary to the endogenous miRNA (wt) or with a 4-base mutation in the seed sequence (mut). c Luciferase activity of sensor constructs cotransfected with 5 nM of the specific miRNA antisense LNA molecule. *p < 0.05, **p < 0.01, Student’s t test (GIF 1 kb)

Fig. S2

Levels of miR-15/107 miRNA expression in AD and control brain tissues. The expression levels of miR-15/107 miRNAs in three different brain areas (temporal cortex, hippocampus, and cerebellum) of AD patients (n = 12) and controls (n = 12) are represented as relative expression to the small nucleolar RNA RNU6B (GIF 352 bytes)

Fig. S3

Levels of CDK5R1 and BACE1 expression in AD and control brain tissues. The expression levels of CDK5R1 and BACE1 genes in three different brain areas (temporal cortex, hippocampus, and cerebellum) of AD patients (n = 12) and controls (n = 12) are represented as relative expression to the SYP gene. *p < 0.05, Student’s t test (GIF 725 bytes)

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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 54, 4329–4342 (2017). https://doi.org/10.1007/s12035-016-0002-4

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