1 5408 129 REGULATION AND SIGNALING OF THE GPR17 RECEPTOR IN OLIGODENDROGLIAL CELLS. REMYELINATION, NAMELY, THE FORMATION OF NEW MYELIN SHEATHS AROUND DENUDED AXONS, COUNTERACTS AXONAL DEGENERATION AND RESTORES NEURONAL FUNCTION. CONSIDERABLE ADVANCES HAVE BEEN MADE IN UNDERSTANDING THIS REGENERATIVE PROCESS THAT OFTEN FAILS IN DISEASES LIKE MULTIPLE SCLEROSIS, LEAVING AXONS DEMYELINATED AND VULNERABLE TO DAMAGE, THUS CONTRIBUTING TO DISEASE PROGRESSION. THE IDENTIFICATION OF THE MEMBRANE RECEPTOR GPR17 ON A SUBSET OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH MEDIATE REMYELINATION IN THE ADULT CENTRAL NERVOUS SYSTEM (CNS), HAS LED TO A HUGE AMOUNT OF EVIDENCE THAT VALIDATED THIS RECEPTOR AS A NEW ATTRACTIVE TARGET FOR REMYELINATING THERAPIES. HERE, WE SUMMARIZE THE ROLE OF GPR17 IN OPC FUNCTION, MYELINATION AND REMYELINATION, DESCRIBING ITS ATYPICAL PHARMACOLOGY, ITS DOWNSTREAM SIGNALING, AND THE GENETIC AND EPIGENETIC FACTORS MODULATING ITS ACTIVITY. WE ALSO HIGHLIGHT CRUCIAL INSIGHTS INTO GPR17 PATHOPHYSIOLOGY COMING FROM THE DEMONSTRATION THAT OLIGODENDROCYTE INJURY, ASSOCIATED WITH INFLAMMATION IN CHRONIC NEURODEGENERATIVE CONDITIONS, IS INVARIABLY CHARACTERIZED BY ABNORMAL AND PERSISTENT GPR17 UPREGULATION, WHICH, IN TURN, IS ACCOMPANIED BY A BLOCK OF OPCS AT IMMATURE PREMYELINATING STAGES. FINALLY, WE DISCUSS THE CURRENT LITERATURE IN LIGHT OF THE POTENTIAL EXPLOITMENT OF GPR17 AS A THERAPEUTIC TARGET TO PROMOTE REMYELINATION. 2020 2 4470 35 MOLECULAR NEUROPATHOLOGY OF ASTROCYTES AND OLIGODENDROCYTES IN ALCOHOL USE DISORDERS. POSTMORTEM STUDIES REVEAL STRUCTURAL AND MOLECULAR ALTERATIONS OF ASTROCYTES AND OLIGODENDROCYTES IN BOTH THE GRAY AND WHITE MATTER (GM AND WM) OF THE PREFRONTAL CORTEX (PFC) IN HUMAN SUBJECTS WITH CHRONIC ALCOHOL ABUSE OR DEPENDENCE. THESE GLIAL CELLULAR CHANGES APPEAR TO PARALLEL AND MAY LARGELY EXPLAIN STRUCTURAL AND FUNCTIONAL ALTERATIONS DETECTED USING NEUROIMAGING TECHNIQUES IN SUBJECTS WITH ALCOHOL USE DISORDERS (AUDS). MOREOVER, DUE TO THE CRUCIAL ROLES OF ASTROCYTES AND OLIGODENDROCYTES IN NEUROTRANSMISSION AND SIGNAL CONDUCTION, THESE CELLS ARE VERY LIKELY MAJOR PLAYERS IN THE MOLECULAR MECHANISMS UNDERPINNING ALCOHOLISM-RELATED CONNECTIVITY DISTURBANCES BETWEEN THE PFC AND RELEVANT INTERCONNECTING BRAIN REGIONS. THE GLIA-MEDIATED ETIOLOGY OF ALCOHOL-RELATED BRAIN DAMAGE IS LIKELY MULTIFACTORIAL SINCE METABOLIC, HORMONAL, HEPATIC AND HEMODYNAMIC FACTORS AS WELL AS DIRECT ACTIONS OF ETHANOL OR ITS METABOLITES HAVE THE POTENTIAL TO DISRUPT DISTINCT ASPECTS OF GLIAL NEUROBIOLOGY. STUDIES IN ANIMAL MODELS OF ALCOHOLISM AND POSTMORTEM HUMAN BRAINS HAVE IDENTIFIED ASTROCYTE MARKERS ALTERED IN RESPONSE TO SIGNIFICANT EXPOSURES TO ETHANOL OR DURING ALCOHOL WITHDRAWAL, SUCH AS GAP-JUNCTION PROTEINS, GLUTAMATE TRANSPORTERS OR ENZYMES RELATED TO GLUTAMATE AND GAMMA-AMINOBUTYRIC ACID (GABA) METABOLISM. CHANGES IN THESE PROTEINS AND THEIR REGULATORY PATHWAYS WOULD NOT ONLY CAUSE GM NEURONAL DYSFUNCTION, BUT ALSO DISTURBANCES IN THE ABILITY OF WM AXONS TO CONVEY IMPULSES. IN ADDITION, ALCOHOLISM ALTERS THE EXPRESSION OF ASTROCYTE AND MYELIN PROTEINS AND OF OLIGODENDROCYTE TRANSCRIPTION FACTORS IMPORTANT FOR THE MAINTENANCE AND PLASTICITY OF MYELIN SHEATHS IN WM AND GM. THESE CHANGES ARE CONCOMITANT WITH EPIGENETIC DNA AND HISTONE MODIFICATIONS AS WELL AS ALTERATIONS IN REGULATORY MICRORNAS (MIRNAS) THAT LIKELY CAUSE PROFOUND DISTURBANCES OF GENE EXPRESSION AND PROTEIN TRANSLATION. KNOWLEDGE IS ALSO AVAILABLE ABOUT INTERACTIONS BETWEEN ASTROCYTES AND OLIGODENDROCYTES NOT ONLY AT THE NODES OF RANVIER (NR), BUT ALSO IN GAP JUNCTION-BASED ASTROCYTE-OLIGODENDROCYTE CONTACTS AND OTHER FORMS OF CELL-TO-CELL COMMUNICATION NOW UNDERSTOOD TO BE CRITICAL FOR THE MAINTENANCE AND FORMATION OF MYELIN. CLOSE INTERACTIONS BETWEEN ASTROCYTES AND OLIGODENDROCYTES ALSO SUGGEST THAT THERAPIES FOR ALCOHOLISM BASED ON A SPECIFIC GLIAL CELL TYPE PATHOLOGY WILL REQUIRE A BETTER UNDERSTANDING OF MOLECULAR INTERACTIONS BETWEEN DIFFERENT CELL TYPES, AS WELL AS CONSIDERING THE POSSIBILITY OF USING COMBINED MOLECULAR APPROACHES FOR MORE EFFECTIVE THERAPIES. 2018 3 80 44 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES. 2016 4 2882 47 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 5 3135 33 GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN PBMCS ARE ALTERED IN RRMS PATIENTS TREATED WITH IFN-BETA AND GA-A PRELIMINARY STUDY. MULTIPLE SCLEROSIS (MS) IS A CHRONIC DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM (CNS) DUE TO AN AUTOIMMUNE ATTACK ON AXONAL MYELIN SHEATHS. EPIGENETICS IS AN OPEN RESEARCH TOPIC ON MS, WHICH HAS BEEN INVESTIGATED IN SEARCH OF BIOMARKERS AND TREATMENT TARGETS FOR THIS HETEROGENEOUS DISEASE. IN THIS STUDY, WE QUANTIFIED GLOBAL LEVELS OF EPIGENETIC MARKS USING AN ELISA-LIKE APPROACH IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM 52 PATIENTS WITH MS, TREATED WITH INTERFERON BETA (IFN-BETA) AND GLATIRAMER ACETATE (GA) OR UNTREATED, AND 30 HEALTHY CONTROLS. WE PERFORMED MEDIA COMPARISONS AND CORRELATION ANALYSES OF THESE EPIGENETIC MARKERS WITH CLINICAL VARIABLES IN SUBGROUPS OF PATIENTS AND CONTROLS. WE OBSERVED THAT DNA METHYLATION (5-MC) DECREASED IN TREATED PATIENTS COMPARED WITH UNTREATED AND HEALTHY CONTROLS. MOREOVER, 5-MC AND HYDROXYMETHYLATION (5-HMC) CORRELATED WITH CLINICAL VARIABLES. IN CONTRAST, HISTONE H3 AND H4 ACETYLATION DID NOT CORRELATE WITH THE DISEASE VARIABLES CONSIDERED. GLOBALLY QUANTIFIED EPIGENETIC DNA MARKS 5-MC AND 5-HMC CORRELATE WITH DISEASE AND WERE ALTERED WITH TREATMENT. HOWEVER, TO DATE, NO BIOMARKER HAS BEEN IDENTIFIED THAT CAN PREDICT THE POTENTIAL RESPONSE TO THERAPY BEFORE TREATMENT INITIATION. 2023 6 2856 35 FROM METHYLATION TO MYELINATION: EPIGENOMIC AND TRANSCRIPTOMIC PROFILING OF CHRONIC INACTIVE DEMYELINATED MULTIPLE SCLEROSIS LESIONS. IN THE PROGRESSIVE PHASE OF MULTIPLE SCLEROSIS (MS), THE HAMPERED DIFFERENTIATION CAPACITY OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS) EVENTUALLY RESULTS IN REMYELINATION FAILURE. WE HAVE PREVIOUSLY SHOWN THAT DNA METHYLATION OF ID2/ID4 IS HIGHLY INVOLVED IN OPC DIFFERENTIATION AND REMYELINATION. IN THIS STUDY, WE TOOK AN UNBIASED APPROACH BY DETERMINING GENOME-WIDE DNA METHYLATION PATTERNS WITHIN CHRONICALLY DEMYELINATED MS LESIONS AND INVESTIGATED HOW CERTAIN EPIGENETIC SIGNATURES RELATE TO OPC DIFFERENTIATION CAPACITY. WE COMPARED GENOME-WIDE DNA METHYLATION AND TRANSCRIPTIONAL PROFILES BETWEEN CHRONICALLY DEMYELINATED MS LESIONS AND MATCHED NORMAL-APPEARING WHITE MATTER (NAWM), MAKING USE OF POST-MORTEM BRAIN TISSUE (N = 9/GROUP). DNA METHYLATION DIFFERENCES THAT INVERSELY CORRELATED WITH MRNA EXPRESSION OF THEIR CORRESPONDING GENES WERE VALIDATED FOR THEIR CELL-TYPE SPECIFICITY IN LASER-CAPTURED OPCS USING PYROSEQUENCING. THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM WAS USED TO EPIGENETICALLY EDIT HUMAN-IPSC-DERIVED OLIGODENDROCYTES TO ASSESS THE EFFECT ON CELLULAR DIFFERENTIATION. OUR DATA SHOW HYPERMETHYLATION OF CPGS WITHIN GENES THAT CLUSTER IN GENE ONTOLOGIES RELATED TO MYELINATION AND AXON ENSHEATHMENT. CELL TYPE-SPECIFIC VALIDATION INDICATES A REGION-DEPENDENT HYPERMETHYLATION OF MBP, ENCODING FOR MYELIN BASIC PROTEIN, IN OPCS OBTAINED FROM WHITE MATTER LESIONS COMPARED TO NAWM-DERIVED OPCS. BY ALTERING THE DNA METHYLATION STATE OF SPECIFIC CPGS WITHIN THE PROMOTOR REGION OF MBP, USING EPIGENETIC EDITING, WE SHOW THAT CELLULAR DIFFERENTIATION AND MYELINATION CAN BE BIDIRECTIONALLY MANIPULATED USING THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM IN VITRO. OUR DATA INDICATE THAT OPCS WITHIN CHRONICALLY DEMYELINATED MS LESIONS ACQUIRE AN INHIBITORY PHENOTYPE, WHICH TRANSLATES INTO HYPERMETHYLATION OF CRUCIAL MYELINATION-RELATED GENES. ALTERING THE EPIGENETIC STATUS OF MBP CAN RESTORE THE DIFFERENTIATION CAPACITY OF OPCS AND POSSIBLY BOOST (RE)MYELINATION. 2023 7 4758 47 NOVEL TREATMENT STRATEGIES TARGETING MYELIN AND OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA. OLIGODENDROCYTES ARE THE GLIAL CELLS RESPONSIBLE FOR THE FORMATION OF THE MYELIN SHEATH AROUND AXONS. DURING NEURODEVELOPMENT, OLIGODENDROCYTES UNDERGO MATURATION AND DIFFERENTIATION, AND LATER REMYELINATION IN ADULTHOOD. ABNORMALITIES IN THESE PROCESSES HAVE BEEN ASSOCIATED WITH BEHAVIORAL AND COGNITIVE DYSFUNCTIONS AND THE DEVELOPMENT OF VARIOUS MENTAL ILLNESSES LIKE SCHIZOPHRENIA. SEVERAL STUDIES HAVE IMPLICATED OLIGODENDROCYTE DYSFUNCTION AND MYELIN ABNORMALITIES IN THE DISORDER, TOGETHER WITH ALTERED EXPRESSION OF MYELIN-RELATED GENES SUCH AS OLIG2, CNP, AND NRG1. HOWEVER, THE MOLECULAR MECHANISMS SUBJACENT OF THESE ALTERATIONS REMAIN ELUSIVE. SCHIZOPHRENIA IS A SEVERE, CHRONIC PSYCHIATRIC DISORDER AFFECTING MORE THAN 23 MILLION INDIVIDUALS WORLDWIDE AND ITS SYMPTOMS USUALLY APPEAR AT THE BEGINNING OF ADULTHOOD. CURRENTLY, THE MAJOR THERAPEUTIC STRATEGY FOR SCHIZOPHRENIA RELIES ON THE USE OF ANTIPSYCHOTICS. DESPITE THEIR WIDESPREAD USE, THE EFFECTS OF ANTIPSYCHOTICS ON GLIAL CELLS, ESPECIALLY OLIGODENDROCYTES, REMAIN UNCLEAR. THUS, IN THIS REVIEW WE HIGHLIGHT THE CURRENT KNOWLEDGE REGARDING OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA, COMPILING DATA FROM (EPI)GENETIC STUDIES AND UP-TO-DATE MODELS TO INVESTIGATE THE ROLE OF OLIGODENDROCYTES IN THE DISORDER. IN ADDITION, WE EXAMINED POTENTIAL TARGETS CURRENTLY INVESTIGATED FOR THE IMPROVEMENT OF SCHIZOPHRENIA SYMPTOMS. RESEARCH IN THIS AREA HAS BEEN INVESTIGATING POTENTIAL BENEFICIAL COMPOUNDS, INCLUDING THE D-AMINO ACIDS D-ASPARTATE AND D-SERINE, THAT ACT AS NMDA RECEPTOR AGONISTS, MODULATING THE GLUTAMATERGIC SIGNALING; THE ANTIOXIDANT N-ACETYLCYSTEINE, A PRECURSOR IN THE SYNTHESIS OF GLUTATHIONE, PROTECTING AGAINST THE REDOX IMBALANCE; AS WELL AS LITHIUM, AN INHIBITOR OF GLYCOGEN SYNTHASE KINASE 3BETA (GSK3BETA) SIGNALING, CONTRIBUTING TO OLIGODENDROCYTE SURVIVAL AND FUNCTIONING. IN CONCLUSION, THERE IS STRONG EVIDENCE LINKING OLIGODENDROCYTE DYSFUNCTION TO THE DEVELOPMENT OF SCHIZOPHRENIA. HENCE, A BETTER UNDERSTANDING OF OLIGODENDROCYTE DIFFERENTIATION, AS WELL AS THE EFFECTS OF ANTIPSYCHOTIC MEDICATION IN THESE CELLS, COULD HAVE POTENTIAL IMPLICATIONS FOR UNDERSTANDING THE DEVELOPMENT OF SCHIZOPHRENIA AND FINDING NEW TARGETS FOR DRUG DEVELOPMENT. 2020 8 741 33 CANDIDATE GENES OF WALDENSTROM'S MACROGLOBULINEMIA: CURRENT EVIDENCE AND RESEARCH. WALDENSTROM'S MACROGLOBULINEMIA (WM) IS A RELATIVELY UNCOMMON, INDOLENT MALIGNANCY OF IMMUNOGLOBULIN M-PRODUCING B CELLS. THE WORLD HEALTH ORGANIZATION CLASSIFIES IT AS A LYMPHOPLASMACYTIC LYMPHOMA AND PATIENTS TYPICALLY PRESENT WITH ANEMIA, HEPATOSPLENOMEGALY AND DIFFUSE LYMPHADENOPATHIES. HISTORICALLY, THE GENETIC CHARACTERIZATION OF THE DISEASE HAS BEEN HAMPERED BY THE RELATIVELY LOW PROLIFERATIVE RATE OF WM CELLS, THUS MAKING KARYOTYPING CHALLENGING. THE USE OF NOVEL TECHNOLOGIES SUCH AS FLUORESCENCE IN SITU HYBRIDIZATION, GENE ARRAY, AND WHOLE GENOME SEQUENCING HAS CONTRIBUTED GREATLY TO ESTABLISHING CANDIDATE GENES IN THE PATHOPHYSIOLOGY OF WM AND TO IDENTIFYING POTENTIAL TREATMENT TARGETS, SUCH AS L265P MYD88. THE DISCOVERY OF MICRORNAS AND THE RECOGNITION OF EPIGENETICS AS A MAJOR MODULATORY MECHANISM OF ONCOGENE EXPRESSION AND/OR ONCOSUPPRESSOR SILENCING HAVE AIDED IN FURTHER UNDERSTANDING THE PATHOGENESIS OF WM. ONCE THOUGHT TO CLOSELY RESEMBLE MULTIPLE MYELOMA, A CANCER OF TERMINALLY DIFFERENTIATED, IMMUNOGLOBULIN-SECRETING PLASMA CELLS, WM APPEARS TO GENETICALLY CLUSTER WITH OTHER INDOLENT B-CELL LYMPHOMAS SUCH AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL CELL LYMPHOMA. THE RELATIVE HIGH INCIDENCE OF FAMILIAL CASES OF WM AND OTHER B-CELL MALIGNANCIES HAS BEEN HELPFUL IN IDENTIFYING HIGH-RISK GENE CANDIDATES. IN THIS REVIEW, WE FOCUS ON THE ESTABLISHED GENES INVOLVED IN THE PATHOGENESIS OF WM, WITH SPECIAL EMPHASIS ON THE KEY ROLE OF DERANGEMENT OF THE NUCLEAR FACTOR KAPPA B SIGNALING PATHWAY AND EPIGENETIC MECHANISMS. 2013 9 5426 41 REGULATION OF SIRTUIN EXPRESSION IN AUTOIMMUNE NEUROINFLAMMATION: INDUCTION OF SIRT1 IN OLIGODENDROCYTE PROGENITOR CELLS. IN MULTIPLE SCLEROSIS (MS) REGENERATION OF OLIGODENDROCYTES FOLLOWING INFLAMMATORY DEMYELINATION IS LIMITED BY THE COMPROMISED ABILITY OF PROGENITORS TO REPOPULATE LESIONED AREAS AND TRANSITION TO FUNCTIONALLY COMPETENT OLIGODENDROCYTES. REGARDING UNDERLYING MECHANISMS, THE INVOLVEMENT OF EPIGENETIC PROCESSES HAS BEEN SUGGESTED, E.G. THE CONTRIBUTION OF HISTONE DEACETYLASES (HDAC) KNOWN TO REGULATE OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION. HOWEVER, THEIR PRECISE EXPRESSION PATTERNS, PARTICULAR OF REDOX-SENSITIVE NAD(+) HDACS, REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DETERMINED THE EXPRESSION AND ACTIVITY OF SIRTUINS, MEMBERS OF THE HDAC CLASS III FAMILY WITH A SPECIFIC FOCUS ON SIRT1, PREVIOUSLY ASSOCIATED WITH NEURODEGENERATIVE, INFLAMMATORY AND DEMYELINATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS). BY INVESTIGATING MOUSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MODEL FOR MS, WE FOUND THAT TRANSCRIPTION OF SIRT1, SIRT2 AND SIRT6 WAS SIGNIFICANTLY INCREASED IN THE CNS DURING CHRONIC DISEASE STAGES. WE CONFIRMED THIS FINDING FOR SIRT1 PROTEIN EXPRESSION AND WERE ABLE TO LOCALIZE UPREGULATED SIRT1 IN NUCLEI OF NG2(+) OR PDGFRALPHA(+) OPCS IN DEMYELINATED BRAIN LESIONS. IN CULTURED MOUSE A2B5(+) OPCS BLOCKADE OF SIRT1 ACTIVITY BY THE SMALL MOLECULE COMPOUND EX527 ENHANCED MITOTIC ACTIVITY BUT DID NOT AFFECT THE CAPACITY TO DIFFERENTIATE. A SIMILAR PATTERN WAS DETECTABLE IN OPCS DERIVED FROM SIRT1-DEFICIENT ANIMALS. TAKEN TOGETHER, OUR DATA SUGGEST THAT SIRT1 INHIBITION MAY HELP TO EXPAND THE ENDOGENOUS POOL OF OPCS WITHOUT AFFECTING THEIR DIFFERENTIATION. 2019 10 6531 41 TRANSCRIPTIONAL REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) BY METHYL CPG BINDING PROTEIN 2 (MECP2): A NOVEL MECHANISM FOR RE-MYELINATION AND/OR MYELIN REPAIR INVOLVED IN THE TREATMENT OF MULTIPLE SCLEROSIS (MS). MULTIPLE SCLEROSIS (MS) IS A CHRONIC PROGRESSIVE, NEUROLOGICAL DISEASE CHARACTERIZED BY THE TARGETED IMMUNE SYSTEM-MEDIATED DESTRUCTION OF CENTRAL NERVOUS SYSTEM (CNS) MYELIN. AUTOREACTIVE CD4+ T HELPER CELLS HAVE A KEY ROLE IN ORCHESTRATING MS-INDUCED MYELIN DAMAGE. ONCE ACTIVATED, CIRCULATING TH1-CELLS SECRETE A VARIETY OF INFLAMMATORY CYTOKINES THAT FOSTER THE BREAKDOWN OF BLOOD-BRAIN BARRIER (BBB) EVENTUALLY INFILTRATING INTO THE CNS. INSIDE THE CNS, THEY BECOME REACTIVATED UPON EXPOSURE TO THE MYELIN STRUCTURAL PROTEINS AND CONTINUE TO PRODUCE INFLAMMATORY CYTOKINES SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) THAT LEADS TO DIRECT ACTIVATION OF ANTIBODIES AND MACROPHAGES THAT ARE INVOLVED IN THE PHAGOCYTOSIS OF MYELIN. PROLIFERATING OLIGODENDROCYTE PRECURSORS (OPS) MIGRATING TO THE LESION SITES ARE CAPABLE OF ACUTE REMYELINATION BUT UNABLE TO COMPLETELY REPAIR OR RESTORE THE IMMUNE SYSTEM-MEDIATED MYELIN DAMAGE. THIS RESULTS IN VARIOUS PERMANENT CLINICAL NEUROLOGICAL DISABILITIES SUCH AS COGNITIVE DYSFUNCTION, FATIGUE, BOWEL/BLADDER ABNORMALITIES, AND NEUROPATHIC PAIN. AT PRESENT, THERE IS NO CURE FOR MS. RECENT REMYELINATION AND/OR MYELIN REPAIR STRATEGIES HAVE FOCUSED ON THE ROLE OF THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS UPSTREAM TRANSCRIPTIONAL REPRESSOR METHYL CPG BINDING PROTEIN (MECP2). RESEARCH IN THE FIELD OF EPIGENETIC THERAPEUTICS INVOLVING HISTONE DEACETYLASE (HDAC) INHIBITORS AND LYSINE ACETYL TRANSFERASE (KAT) INHIBITORS IS BEING EXPLORED TO REPRESS THE DETRIMENTAL EFFECTS OF MECP2. THIS REVIEW WILL ADDRESS THE ROLE OF MECP2 AND BDNF IN REMYELINATION AND/OR MYELIN REPAIR AND THE POTENTIAL OF HDAC AND KAT INHIBITORS AS NOVEL THERAPEUTIC INTERVENTIONS FOR MS. 2016 11 1179 29 CONVERGENCE AND DIVERGENCE IN THE ETIOLOGY OF MYELIN IMPAIRMENT IN PSYCHIATRIC DISORDERS AND DRUG ADDICTION. IMPAIRMENT OF OLIGODENDROGLIA (OL)-DEPENDENT MYELINATION IN THE CENTRAL NERVOUS SYSTEM (CNS) IS A REMARKABLE PARALLEL RECENTLY IDENTIFIED IN MAJOR PSYCHIATRIC DISORDERS AND CHRONIC DRUG ABUSE. NEUROIMAGING AND NEUROPATHOLOGICAL STUDIES REVEALED MYELIN DEFECTS AND MICROARRAY-PROFILING ANALYSIS DEMONSTRATED ABERRANT EXPRESSION OF MYELIN-RELATED GENES IN SCHIZOPHRENIA (SZ), BIPOLAR DISORDER (BD), MAJOR DEPRESSIVE DISORDER (MDD) AND COCAINE ADDICTION. HOWEVER, THE ETIOLOGY UNDERLYING MYELIN IMPAIRMENT IN THESE CLINICALLY DISTINCT SUBJECTS REMAINS ELUSIVE. THIS ARTICLE REVIEWS MYELIN IMPAIRMENT IN LINE WITH DOPAMINERGIC DYSFUNCTION, A PRIME NEUROPATHOPHYSIOLOGICAL TRAIT SHARED IN PSYCHIATRIC DISORDERS AND DRUG ABUSE, AS WELL AS THE GENETIC AND EPIGENETIC ALTERATIONS ASSOCIATED WITH THESE DISEASES. THE CURRENT FINDINGS SUPPORT THE HYPOTHESIS THAT ABERRANT DOPAMINE (DA) ACTION ON OLS IS A COMMON PATHOLOGIC MECHANISM FOR MYELIN IMPAIRMENT IN THE AFOREMENTIONED MENTAL MORBIDITIES, WHEREAS INHERITED GENETIC VARIATIONS THAT SPECIFICALLY AFFECT OL DEVELOPMENT AND MYELINOGENESIS MAY FURTHER INCREASE MYELIN VULNERABILITY IN PSYCHIATRIC DISORDERS. IMPORTANTLY, OL DEFECT IS NOT ONLY A PATHOLOGICAL CONSEQUENCE BUT ALSO A CAUSATIVE FACTOR FOR DOPAMINERGIC DYSFUNCTION. HENCE, MYELIN IMPAIRMENT IS A KEY FACTOR IN THE PATHOGENIC LOOP OF PSYCHIATRIC DISEASES AND DRUG ADDICTION. 2008 12 4304 44 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. 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. 2019 13 4721 40 NONCODING RNAS IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS CHARACTERIZED BY AXONAL DEGENERATION AND GLIOSIS. ALTHOUGH THE CAUSES OF MS REMAIN UNKNOWN, GENE DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM HAS BEEN ASSOCIATED WITH THE DISEASE PATHOGENESIS. AS SUCH, THE VARIOUS REGULATORS OF GENE EXPRESSION MAY BE CONTRIBUTING FACTORS. THE NONCODING (NC) RNAS HAVE PIQUED THE INTEREST OF MS RESEARCHERS DUE TO THEIR KNOWN FUNCTIONS IN HUMAN PHYSIOLOGY AND VARIOUS PATHOLOGICAL PROCESSES, DESPITE BEING GENERALLY CHARACTERIZED AS TRANSCRIPTS WITHOUT APPARENT PROTEIN-CODING CAPACITY. ACCUMULATING EVIDENCE HAS INDICATED THAT NCRNAS PARTICIPATE IN THE REGULATION OF MS BY ACTING AS EPIGENETIC FACTORS, ESPECIALLY THE LONG (L) NCRNAS AND THE MICRO (MI) RNAS, AND THEY ARE NOW RECOGNIZED AS KEY REGULATORY MOLECULES IN MS. IN THIS REVIEW, WE SUMMARIZE THE MOST CURRENT STUDIES ON THE CONTRIBUTION OF NCRNAS IN MS PATHOGENIC PROCESSES AND DISCUSS THEIR POTENTIAL APPLICATIONS IN THE DIAGNOSIS AND TREATMENT OF MS. 2018 14 4982 37 PATHOPHYSIOLOGY OF THE BLOOD-BRAIN BARRIER: ANIMAL MODELS AND METHODS. THE SPECIALIZED CEREBRAL MICROVASCULAR ENDOTHELIUM INTERACTS WITH THE CELLULAR MILIEU OF THE BRAIN AND EXTRACELLULAR MATRIX TO FORM A NEUROVASCULAR UNIT, ONE ASPECT OF WHICH IS A REGULATED INTERFACE BETWEEN THE BLOOD AND CENTRAL NERVOUS SYSTEM (CNS). THE CONCEPT OF THIS BLOOD-BRAIN BARRIER (BBB) AS A DYNAMICALLY REGULATED SYSTEM RATHER THAN A STATIC BARRIER HAS WIDE-RANGING IMPLICATIONS FOR PATHOPHYSIOLOGY OF THE CNS. WHILE IN VITRO MODELS OF THE BBB ARE USEFUL FOR SCREENING DRUGS TARGETED TO THE CNS AND INDISPENSABLE FOR STUDIES OF CEREBRAL ENDOTHELIAL CELL BIOLOGY, THE COMPLEX INTERACTIONS OF THE NEUROVASCULAR UNIT MAKE ANIMAL-BASED MODELS AND METHODS ESSENTIAL TOOLS FOR UNDERSTANDING THE PATHOPHYSIOLOGY OF THE BBB. BBB DYSFUNCTION IS A COMPLICATION OF NEURODEGENERATIVE DISEASE AND BRAIN INJURY. STUDIES ON ANIMAL MODELS HAVE SHOWN THAT DISEASES OF THE PERIPHERY, SUCH AS DIABETES AND INFLAMMATORY PAIN, HAVE DELETERIOUS EFFECTS ON THE BBB WHICH MAY CONTRIBUTE TO NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH THESE CONDITIONS. FURTHERMORE, GENETIC AND/OR EPIGENETIC ABNORMALITIES IN CONSTITUENTS OF THE BBB MAY BE SIGNIFICANT CONTRIBUTING FACTORS IN DISEASE ETIOLOGY. RESEARCH THAT APPROACHES THE BBB AS A DYNAMIC SYSTEM INTEGRATED WITH BOTH THE CNS AND THE PERIPHERY IS THEREFORE CRITICAL TO UNDERSTANDING AND TREATING DISEASES OF THE CNS. HEREIN, WE REVIEW VARIOUS METHODOLOGICAL APPROACHES USED TO STUDY BBB FUNCTION IN THE CONTEXT OF DISEASE. THESE INCLUDE MEASUREMENT OF TRANSPORT BETWEEN BLOOD AND BRAIN, IMAGING-BASED TECHNOLOGIES, AND GENOMIC/PROTEOMIC APPROACHES. 2008 15 4269 30 MICROBIAL DYSBIOSIS AND LACK OF SCFA PRODUCTION IN A SPANISH COHORT OF PATIENTS WITH MULTIPLE SCLEROSIS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, DEMYELINATING, AND IMMUNE-MEDIATED DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE INCIDENCE OF MS HAS INCREASED IN THE PAST SEVERAL DECADES, SUGGESTING CHANGES IN THE ENVIRONMENTAL RISK FACTORS. MUCH EFFORT HAS BEEN MADE IN THE DESCRIPTION OF THE GUT MICROBIOTA IN MS; HOWEVER, LITTLE IS KNOWN ABOUT THE DYSBIOSIS ON ITS FUNCTION. THE MICROBIOTA PRODUCES THOUSANDS OF BIOLOGICALLY ACTIVE SUBSTANCES AMONG WHICH ARE NOTABLE THE SHORT-CHAIN FATTY ACID (SCFA) EXCRETION. OBJECTIVES: ANALYZE THE INTERACTION BETWEEN MICROBIOTA, SCFAS, DIET, AND MS. METHODS: 16S, NUTRITIONAL QUESTIONNAIRES, AND SCFAS QUANTIFICATION HAVE BEEN RECOVERED FROM MS PATIENTS AND CONTROLS. RESULTS: OUR RESULTS REVEALED AN INCREMENT IN THE PHYLUM PROTEOBACTERIA, ESPECIALLY THE FAMILY ENTEROBACTERIACEAE, A LACK IN TOTAL SCFA EXCRETION, AND AN ALTERED PROFILE OF SCFAS IN A SPANISH COHORT OF MS PATIENTS. THESE ALTERATIONS ARE MORE EVIDENT IN PATIENTS WITH HIGHER DISABILITY. CONCLUSIONS: THE ABUNDANCE OF PROTEOBACTERIA AND ACETATE AND THE LOW EXCRETION OF TOTAL SCFAS, ESPECIALLY BUTYRATE, ARE COMMON CHARACTERISTICS OF MS PATIENTS, AND BESIDES, BOTH ARE ASSOCIATED WITH A WORSE PROGNOSIS OF THE DISEASE. 2022 16 5280 32 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 17 3888 39 KLOTHO PATHWAYS, MYELINATION DISORDERS, NEURODEGENERATIVE DISEASES, AND EPIGENETIC DRUGS. IN THIS REVIEW WE OUTLINE A RATIONALE FOR IDENTIFYING NEUROPROTECTANTS AIMED AT INDUCING ENDOGENOUS KLOTHO ACTIVITY AND EXPRESSION, WHICH IS EPIGENETIC ACTION, BY DEFINITION. SUCH AN APPROACH SHOULD PROMOTE REMYELINATION AND/OR STIMULATE MYELIN REPAIR BY ACTING ON MITOCHONDRIAL FUNCTION, THEREBY HERALDING A LIFE-SAVING PATH FORWARD FOR PATIENTS SUFFERING FROM NEUROINFLAMMATORY DISEASES. DISORDERS OF MYELIN IN THE NERVOUS SYSTEM DAMAGE THE TRANSMISSION OF SIGNALS, RESULTING IN LOSS OF VISION, MOTION, SENSATION, AND OTHER FUNCTIONS DEPENDING ON THE AFFECTED NERVES, CURRENTLY WITH NO EFFECTIVE TREATMENT. KLOTHO GENES AND THEIR SINGLE-PASS TRANSMEMBRANE KLOTHO PROTEINS ARE POWERFUL GOVERNORS OF THE THREADS OF LIFE AND DEATH, TRUE TO THE ORIGIN OF THEIR NAME, FATES, IN GREEK MYTHOLOGY. AMONG ITS MANY IMPORTANT FUNCTIONS, KLOTHO IS AN OBLIGATORY CO-RECEPTOR THAT BINDS, ACTIVATES, AND/OR POTENTIATES CRITICAL FIBROBLAST GROWTH FACTOR ACTIVITY. SINCE THE DISCOVERY OF KLOTHO A LITTLE OVER TWO DECADES AGO, IT HAS BECOME EVER MORE APPARENT THAT WHEN KLOTHO PATHWAYS GO AWRY, OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION TAKE OVER, AND AGE-RELATED CHRONIC DISORDERS ARE LIKELY TO FOLLOW. THE PHYSIOLOGICAL CONSEQUENCES CAN BE WIDE RANGING, POTENTIALLY WREAKING HAVOC ON THE BRAIN, EYE, KIDNEY, MUSCLE, AND MORE. CENTRAL NERVOUS SYSTEM DISORDERS, NEURODEGENERATIVE IN NATURE, AND ESPECIALLY THOSE AFFECTING THE MYELIN SHEATH, REPRESENT WORTHY TARGETS FOR ADVANCING THERAPIES THAT ACT UPON KLOTHO PATHWAYS. CURRENT DRUGS FOR THESE DISEASES, EVEN THERAPEUTICS THAT ARE DISEASE MODIFYING RATHER THAN TREATING ONLY THE SYMPTOMS, LEAVE MUCH ROOM FOR IMPROVEMENT. IT IS THUS NO WONDER THAT THIS TOPIC HAS CAUGHT THE ATTENTION OF BIOMEDICAL RESEARCHERS AROUND THE WORLD. 2020 18 6347 34 THE ROLE OF EPIGENETICS IN NEUROINFLAMMATORY-DRIVEN DISEASES. NEURODEGENERATIVE DISORDERS ARE CHARACTERIZED BY THE PROGRESSIVE LOSS OF CENTRAL AND/OR PERIPHERAL NERVOUS SYSTEM NEURONS. WITHIN THIS CONTEXT, NEUROINFLAMMATION COMES UP AS ONE OF THE MAIN FACTORS LINKED TO NEURODEGENERATION PROGRESSION. IN FACT, NEUROINFLAMMATION HAS BEEN RECOGNIZED AS AN OUTSTANDING FACTOR FOR ALZHEIMER'S DISEASE (AD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), PARKINSON'S DISEASE (PD), AND MULTIPLE SCLEROSIS (MS). INTERESTINGLY, NEUROINFLAMMATORY DISEASES ARE CHARACTERIZED BY DRAMATIC CHANGES IN THE EPIGENETIC PROFILE, WHICH MIGHT PROVIDE NOVEL PROGNOSTIC AND THERAPEUTIC FACTORS TOWARDS NEUROINFLAMMATORY TREATMENT. DEEP CHANGES IN DNA AND HISTONE METHYLATION, ALONG WITH HISTONE ACETYLATION AND ALTERED NON-CODING RNA EXPRESSION, HAVE BEEN REPORTED AT THE ONSET OF INFLAMMATORY DISEASES. THE AIM OF THIS WORK IS TO REVIEW THE CURRENT KNOWLEDGE ON THIS FIELD. 2022 19 4536 42 MULTIPLE SCLEROSIS - RISK FACTORS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNOLOGICAL CONDITION OF THE CENTRAL NERVOUS SYSTEM (CNS) AFFECTING MAINLY YOUNG ADULT INDIVIDUALS. THE PREVALENCE RANGES APPROXIMATELY BETWEEN 50 AND 300 PER 100000 INDIVIDUALS. IT IS CHARACTERIZED BY AN INFLAMMATORY PROCESS, DEMYELINATION AND AXONAL LOSS. IMMUNOLOGICAL MECHANISMS RESULTING IN THE DAMAGE TO THE MYELIN SHEATH EFFECTING THEN IN IMPAIRED NERVE IMPULSE CONDUCTION HAVE THE KEY ROLE IN MS PATHOGENESIS. THE ROLE OF INFLAMMATORY FACTORS HAS ALSO BEEN PROVED. HOWEVER, IT HAS NOT BEEN EXPLICITLY SHOWN WHETHER SUCH AN INFLAMMATORY PROCESS IS THE TRIGGERING FACTOR OR SECONDARY TO A YET UNKNOWN INFECTIOUS FACTOR OR A DEGENERATIVE PROCESS OF THE CNS. THEREFORE, RECOGNITION OF THE EPIGENETIC RISK FACTORS, SUCH AS: GEOGRAPHICAL LATITUDE, VITAMIN D LEVEL, HYGIENE HYPOTHESIS, EPSTEIN-BARR VIRUS (EBV) INFECTION AND OTHERS MAY CONTRIBUTE TO BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING MULTIPLE SCLEROSIS. ADDITIONALLY, THEY MAY PROVIDE GUIDELINES FOR MORE EFFICIENT THERAPIES AND BETTER PREVENTION OF THE DISEASE. AIM OF THIS REVIEW IS TO PRESENT MOST CURRENT DATA ON MULTIPLE SCLEROSIS RISK FACTORS, CONSIDERING THOSE LESS KNOWN. 2020 20 2004 32 EPIGENETIC ASPECTS OF MULTIPLE SCLEROSIS AND FUTURE THERAPEUTIC OPTIONS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND NEURODEGENERATIVE DISEASE ACCOMPANIED BY DEMYELINATION OF NEURONS IN THE CENTRAL NERVOUS SYSTEM THAT MOSTLY AFFECTS YOUNG ADULTS, ESPECIALLY WOMEN. THIS DISEASE HAS TWO PHASES INCLUDING RELAPSING-REMITTING FORM (RR-MS) BY EPISODES OF RELAPSE AND PERIODS OF CLINICAL REMISSION AND SECONDARY-PROGRESSIVE FORM (SP-MS), WHICH CAUSES MORE DISABILITY. THE INHERITANCE PATTERN OF MS IS NOT EXACTLY IDENTIFIED AND THERE IS AN AGREEMENT THAT IT HAS A COMPLEX PATTERN WITH AN INTERPLAY AMONG ENVIRONMENTAL, GENETIC AND EPIGENETIC ALTERNATIONS. EPIGENETIC MECHANISMS THAT ARE IDENTIFIED FOR MS PATHOGENESIS ARE DNA METHYLATION, HISTONE MODIFICATION AND SOME MICRORNAS' ALTERNATIONS. SEVERAL CELLULAR PROCESSES INCLUDING APOPTOSIS, DIFFERENTIATION AND EVOLUTION CAN BE MODIFIED ALONG WITH EPIGENETIC CHANGES. SOME ALTERNATIONS ARE ASSOCIATED WITH EPIGENETIC MECHANISMS IN MS PATIENTS AND THESE CHANGES CAN BECOME KEY POINTS FOR MS THERAPY. THEREFORE, THE AIM OF THIS REVIEW WAS TO DISCUSS EPIGENETIC MECHANISMS THAT ARE ASSOCIATED WITH MS PATHOGENESIS AND FUTURE THERAPEUTIC APPROACHES. 2021