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Multiple sclerosis is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the brain, spinal cord and optic nerves. Neuronal damage is triggered by various harmful factors that engage diverse signalling cascades in neurons; thus, therapeutic approaches to protect neurons will need to focus on agents that can target multiple biological processes. We have therefore focused our attention on microRNAs: small non-coding RNAs that primarily function as post-transcriptional regulators that target messenger RNAs and repress their translation into proteins. A single microRNA can target many functionally related messenger RNAs making microRNAs powerful epigenetic regulators. Dysregulation of microRNAs has been described in many neurodegenerative diseases including multiple sclerosis. Here, we report that two microRNAs, miR-223-3p and miR-27a-3p, are upregulated in neurons in the experimental autoimmune encephalomyelitis mouse model of CNS inflammation and in grey matter-containing multiple sclerosis lesions. Prior work has shown peripheral blood mononuclear cell conditioned media causes sublethal degeneration of neurons in culture. We find overexpression of miR-27a-3p or miR-223-3p protects dissociated cortical neurons from condition media mediated degeneration. Introduction of miR-223-3p in vivo in mouse retinal ganglion cells protects their axons from degeneration in experimental autoimmune encephalomyelitis. In silico analysis revealed that messenger RNAs involved in glutamate receptor signalling are enriched as miR-27a-3p and miR-223-3p targets. We observe that antagonism of NMDA and AMPA type glutamate receptors protects neurons from condition media dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by targeting messenger RNAs involved in glutamate receptor signalling.
This article was published in the following journal.
Name: Brain : a journal of neurology
MicroRNA 182 is important for the clonal expansion of CD4 T cells (Th) following IL-2 stimulation and is a potential therapeutic target for autoimmune diseases. In the present study, we investigated t...
Multiple sclerosis (MS) is a chronic and debilitating autoimmune disorder of the central nervous system in which the autoimmune T cells destroy myelin, thus causing lesion, damage, and neuronal dysfun...
Leptomeningeal inflammation, as evidenced by leptomeningeal contrast enhancement (LMCE), is associated to cortical pathology in multiple sclerosis. The temporal pattern of LMCE in experimental autoimm...
Antibodies, including antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1, have been shown to contribute to the pathogenesis of multiple sclerosis, thus it is important to...
Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hy...
Acute disseminated encephalomyelitis is an immune-mediated inflammatory demyelinating disease of the central nervous system, which is typically transitory and self-limiting. It is characte...
Parkinson´s disease is based on a Lewy body degeneration of cerebral and extracerebral neurons. This Lewy body degeneration includes cerebral cholinergic neurons besides dopaminergic neur...
This study seeks to examine the effect of a subcutaneous infusion of CT38, an experimental peptide, on cardio-pulmonary exercise test (CPET) performance and CPET-induced changes in functio...
This study is designed to determine safety of and immune response to Venezuelan Equine Encephalomyelitis Vaccine, Live, Attenuated, Dried TC-83, NDBR-102 (TC-83).
Molecular analysis of the atheroma plaque. Screening for a novel biomarker of carotid status.
Experimental animal models for human AUTOIMMUNE DISEASES OF THE NERVOUS SYSTEM. They include GUILLAIN-BARRE SYNDROME (see NEURITIS, AUTOIMMUNE, EXPERIMENTAL); MYASTHENIA GRAVIS (see MYASTHENIA GRAVIS, AUTOIMMUNE, EXPERIMENTAL); and MULTIPLE SCLEROSIS (see ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL).
An experimental animal model for central nervous system demyelinating disease. Inoculation with a white matter emulsion combined with FREUND'S ADJUVANT, myelin basic protein, or purified central myelin triggers a T cell-mediated immune response directed towards central myelin. The pathologic features are similar to MULTIPLE SCLEROSIS, including perivascular and periventricular foci of inflammation and demyelination. Subpial demyelination underlying meningeal infiltrations also occurs, which is also a feature of ENCEPHALOMYELITIS, ACUTE DISSEMINATED. Passive immunization with T-cells from an afflicted animal to a normal animal also induces this condition. (From Immunol Res 1998;17(1-2):217-27; Raine CS, Textbook of Neuropathology, 2nd ed, p604-5)
A group of 7 proteins produced from a single gene by alternate splicing found in central and peripheral nervous system myelin. The major basic protein (MBP) has long been of interest because it is the antigen, that, when injected into an animal, elicits a cellular immune response that produces the CNS autoimmune disease called experimental allergic encephalomyelitis (ENCEPHALOMYELITIS, ALLERGIC). In the peripheral nervous system, myelin basic protein 18.5-kDa is often referred to as the P1 protein. (From Siegel et al., Basic Neurochemistry, 5th ed, p130, 133)
Diseases characterized by a selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In AMYOTROPHIC LATERAL SCLEROSIS there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes (see MUSCULAR ATROPHY, SPINAL) the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy (BULBAR PALSY, PROGRESSIVE), the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation. (Adams et al., Principles of Neurology, 6th ed, p1089)
Any autoimmune animal disease model used in the study of MYASTHENIA GRAVIS. Injection with purified neuromuscular junction acetylcholine receptor (AChR) (see RECEPTORS, CHOLINERGIC) components results in a myasthenic syndrome that has acute and chronic phases. The motor endplate pathology, loss of acetylcholine receptors, presence of circulating anti-AChR antibodies, and electrophysiologic changes make this condition virtually identical to human myasthenia gravis. Passive transfer of AChR antibodies or lymphocytes from afflicted animals to normals induces passive transfer experimental autoimmune myasthenia gravis. (From Joynt, Clinical Neurology, 1997, Ch 54, p3)
A microRNA (abbreviated miRNA) is a small non-coding RNA molecule (containing about 22 nucleotides) found in plants, animals, and some viruses. Key findings: miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation...
Autoimmune disorders are conditions that occurs when the immune system mistakenly attacks and destroys healthy body tissue. There are more than 80 different types of autoimmune disorders. Normally the immune system's white blood cells help protect ...