Abstract
Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer’s disease (AD) onset and progression. We recently showed that miR-15/107 family can negatively regulate CDK5R1 expression modifying mRNA stability. Interestingly, miRNAs belonging to miR-15/107 family are downregulated in AD brain while CDK5R1 is upregulated. Long non-coding RNAs (lncRNAs) are emerging as master regulators of gene expression, including miRNAs, and their dysregulation has been implicated in the pathogenesis of AD. Here, we evaluated the existence of an additional layer of CDK5R1 expression regulation provided by lncRNAs. In particular, we focused on three lncRNAs potentially regulating CDK5R1 expression levels, based on existing data: NEAT1, HOTAIR, and MALAT1. We demonstrated that NEAT1 and HOTAIR negatively regulate CDK5R1 mRNA levels, while MALAT1 has a positive effect. We also showed that all three lncRNAs positively control miR-15/107 family of miRNAs. Moreover, we evaluated the expression of NEAT1, HOTAIR, and MALAT1 in AD and control brain tissues. Interestingly, NEAT1 displayed increased expression levels in temporal cortex and hippocampus of AD patients. Interestingly, we observed a strong positive correlation between CDK5R1 and NEAT1 expression levels in brain tissues, suggesting a possible neuroprotective role of NEAT1 in AD to compensate for increased CDK5R1 levels. Overall, our work provides evidence of another level of CDK5R1 expression regulation mediated by lncRNAs and points to NEAT1 as a biomarker, as well as a potential pharmacological target for AD therapy.
Highlights
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, causing a severe and permanent impairment of both cognitive and behavioral functions
Our work provides evidence of another level of Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) expression regulation mediated by Long non-coding RNAs (lncRNAs) and points to NEAT1 as a biomarker, as well as a potential pharmacological target for Alzheimer’s disease (AD) therapy
We focused on three different lncRNAs which had the potential for regulating CDK5R1 expression levels and deserved to be analyzed in AD brain tissues, namely NEAT1, HOTAIR, and MALAT1
Summary
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, causing a severe and permanent impairment of both cognitive and behavioral functions. We focused on three different lncRNAs which had the potential for regulating CDK5R1 expression levels and deserved to be analyzed in AD brain tissues, namely NEAT1, HOTAIR, and MALAT1. This observation suggests that in the cerebellum a protective, NEAT1-associated mechanism might efficiently control CDK5R1 levels Another interesting observation is the opposite correlation between the expression of NEAT1 and miR-15/107 miRNAs in AD brains and controls. Since we observed that the silencing of NEAT1, HOTAIR, and MALAT1 lead to a reduction of miR-15/107 miRNAs, we hypothesize that this effect could be mediated by a positive regulatory action of these lncRNAs on transcription factors that promote the expression of this family of miRNAs or, alternatively, by their interaction with the microprocessor to enhance pri-miRNA processing, as already demonstrated for NEAT1 [43]. We show that NEAT1 is upregulated in AD brain, possibly as a part of a protective mechanism against neuronal death, and can be considered a marker of the disease and represents a potential pharmacological target for therapeutic intervention in AD
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