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      Role of MicroRNAs in Parkinson’s Disease

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          Abstract

          Parkinson’s disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood–brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

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          Most cited references86

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          Blood-brain barrier dysfunction in parkinsonian midbrain in vivo.

          Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood-borne chemicals by the blood-brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P-glycoprotein (P-gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P-gp gene. We hypothesized that PD patients have reduced P-gp function in the blood-brain barrier. We used positron emission tomography to measure brain uptake of [(11)C]-verapamil, which is normally extruded from the brain by P-gp. Here, we show significantly elevated uptake of [(11)C]-verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood-brain barrier as a causative mechanism in PD.
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            Parkinson's Disease and Parkinsonism

            Parkinson's disease is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurologic ailment. Male sex and advancing age are independent risk factors and, as the population ages, is taking an increasing toll on productivity and medical resources. There are a number of other extrapyramidal conditions that can make the diagnosis challenging. Unlike other neurodegenerative diseases, idiopathic Parkinson's disease has effective treatments that mitigate symptoms. Medications can improve day-to-day function and, in cases where medication does not give a sustained benefit or has significant side effects, treatments like deep brain stimulation result in improved quality of life.
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              The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.

              Activated oncogenic signaling is central to the development of nearly all forms of cancer, including the most common class of primary brain tumor, glioma. Research over the last two decades has revealed the particular importance of the Akt pathway, and its molecular antagonist PTEN (phosphatase and tensin homolog), in the process of gliomagenesis. Recent studies have also demonstrated that microRNAs (miRNAs) may be responsible for the modulation of cancer-implicated genes in tumors. Here we report the identification miR-26a as a direct regulator of PTEN expression. We also show that miR-26a is frequently amplified at the DNA level in human glioma, most often in association with monoallelic PTEN loss. Finally, we demonstrate that miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                12 November 2019
                November 2019
                : 20
                : 22
                : 5649
                Affiliations
                [1 ]Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore 117594, Singapore; e0054068@ 123456u.nus.edu (S.Y.G.); anthead@ 123456nus.edu.sg (S.T.D.)
                [2 ]National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
                [3 ]Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
                [4 ]Medical Education, Research and Evaluation (MERE) department, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
                [5 ]Neuroscience and Behavioral Disorders (NBD) department, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore
                Author notes
                [* ]Correspondence: chao.yinxia@ 123456singhealth.com.sg (Y.X.C.); tan.eng.king@ 123456singhealth.com.sg (E.-K.T.); anttaysw@ 123456nus.edu.sg (S.S.-W.T.); Tel.: +65-63-214-073 (Y.X.C.); +65-63-214-006 (E.-K.T.); +65-65-163-210 (S.S.-W.T.)
                Article
                ijms-20-05649
                10.3390/ijms20225649
                6888719
                31718095
                f633c54d-0162-4092-a956-ef7c53cb6354
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 October 2019
                : 08 November 2019
                Categories
                Review

                Molecular biology
                parkinson’s disease,micrornas,review
                Molecular biology
                parkinson’s disease, micrornas, review

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