title: The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis.
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.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moncini
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Lunghi
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Valmadre
authors.affiliation: Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Grasso
authors.affiliation: Centre for Integrative Biology, Università degli Studi di Trento, Via Sommarive 9, 38123, Povo, (TN), Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Del Vescovo
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Riva
authors.affiliation: 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.
authors.forename: Michela Alessandra
authors.initials: MA
authors.lastname: Denti
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy. marco.venturin@unimi.it.
authors.forename: Marco
authors.identifier: 0000-0002-5871-9689
authors.initials: M
authors.lastname: Venturin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
chemical_list: C549045:MIRN107 microRNA, human; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; CDK5; CDK5R1/p35; Post-transcriptional regulation; miR-15/107