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      Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases

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          Abstract

          Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell–cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.

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          Most cited references123

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          A MicroRNA feedback circuit in midbrain dopamine neurons.

          MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.
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            Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2.

            RNA editing by site-selective deamination of adenosine to inosine alters codons and splicing in nuclear transcripts, and therefore protein function. ADAR2 (refs 7, 8) is a candidate mammalian editing enzyme that is widely expressed in brain and other tissues, but its RNA substrates are unknown. Here we have studied ADAR2-mediated RNA editing by generating mice that are homozygous for a targeted functional null allele. Editing in ADAR2-/- mice was substantially reduced at most of 25 positions in diverse transcripts; the mutant mice became prone to seizures and died young. The impaired phenotype appeared to result entirely from a single underedited position, as it reverted to normal when both alleles for the underedited transcript were substituted with alleles encoding the edited version exonically. The critical position specifies an ion channel determinant, the Q/R site, in AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor GluR-B pre-messenger RNA. We conclude that this transcript is the physiologically most important substrate of ADAR2.
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              Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

              Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.
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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
                27 June 2019
                July 2019
                : 20
                : 13
                : 3148
                Affiliations
                [1 ]Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
                [2 ]Department of Pathophysiology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
                [3 ]Department of Molecular Neuropathogenesis, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
                Author notes
                [* ]Correspondence: kwak-tky@ 123456umin.ac.jp ; Tel.: +81-3-5841-3566
                Article
                ijms-20-03148
                10.3390/ijms20133148
                6651127
                31252669
                9da8a6e6-a2d9-43ab-8e92-48150773b25a
                © 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
                : 16 May 2019
                : 26 June 2019
                Categories
                Review

                Molecular biology
                neurodegenerative disease,amyotrophic lateral sclerosis (als),rna editing,adenosine deaminase acting on rna 2 (adar2),extracellular rna,biomarker

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