1 3345 98 HISTONE DEACETYLASES AS EPIGENETIC TARGETS FOR TREATING PARKINSON'S DISEASE. PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISEASE THAT IS INCREASINGLY BECOMING A GLOBAL THREAT TO THE HEALTH AND LIFE OF THE ELDERLY WORLDWIDE. ALTHOUGH THERE ARE SOME DRUGS CLINICALLY AVAILABLE FOR TREATING PD, THESE TREATMENTS CAN ONLY ALLEVIATE THE SYMPTOMS OF PD PATIENTS BUT CANNOT COMPLETELY CURE THE DISEASE. THEREFORE, EXPLORING OTHER POTENTIAL MECHANISMS TO DEVELOP MORE EFFECTIVE TREATMENTS THAT CAN MODIFY THE COURSE OF PD IS STILL HIGHLY DESIRABLE. OVER THE LAST TWO DECADES, HISTONE DEACETYLASES, AS AN IMPORTANT GROUP OF EPIGENETIC TARGETS, HAVE ATTRACTED MUCH ATTENTION IN DRUG DISCOVERY. THIS REVIEW FOCUSED ON THE CURRENT KNOWLEDGE ABOUT HISTONE DEACETYLASES INVOLVED IN PD PATHOPHYSIOLOGY AND THEIR INHIBITORS USED IN PD STUDIES. FURTHER PERSPECTIVES RELATED TO SMALL MOLECULES THAT CAN INHIBIT OR DEGRADE HISTONE DEACETYLASES TO TREAT PD WERE ALSO DISCUSSED. 2022 2 5515 31 RILUZOLE ADMINISTRATION TO RATS WITH LEVODOPA-INDUCED DYSKINESIA LEADS TO LOSS OF DNA METHYLATION IN NEURONAL GENES. DYSKINESIAS ARE CHARACTERIZED BY ABNORMAL REPETITIVE INVOLUNTARY MOVEMENTS DUE TO DYSFUNCTIONAL NEURONAL ACTIVITY. ALTHOUGH LEVODOPA-INDUCED DYSKINESIA, CHARACTERIZED BY TIC-LIKE ABNORMAL INVOLUNTARY MOVEMENTS, HAS NO CLINICAL TREATMENT FOR PARKINSON'S DISEASE PATIENTS, ANIMAL STUDIES INDICATE THAT RILUZOLE, WHICH INTERFERES WITH GLUTAMATERGIC NEUROTRANSMISSION, CAN IMPROVE THE PHENOTYPE. THE RAT MODEL OF LEVODOPA-INDUCED DYSKINESIA IS A UNILATERAL LESION WITH 6-HYDROXYDOPAMINE IN THE MEDIAL FOREBRAIN BUNDLE, FOLLOWED BY THE REPEATED ADMINISTRATION OF LEVODOPA. THE MOLECULAR PATHOMECHANISM OF LEVODOPA-INDUCED DYSKINESIA IS STILL NOT DECIPHERED; HOWEVER, THE IMPLICATION OF EPIGENETIC MECHANISMS WAS SUGGESTED. IN THIS STUDY, WE INVESTIGATED THE STRIATUM FOR DNA METHYLATION ALTERATIONS UNDER CHRONIC LEVODOPA TREATMENT WITH OR WITHOUT CO-TREATMENT WITH RILUZOLE. OUR DATA SHOW THAT THE LESIONED AND CONTRALATERAL STRIATA HAVE NEARLY IDENTICAL DNA METHYLATION PROFILES. CHRONIC LEVODOPA AND LEVODOPA + RILUZOLE TREATMENTS LED TO DNA METHYLATION LOSS, PARTICULARLY OUTSIDE OF PROMOTERS, IN GENE BODIES AND CPG POOR REGIONS. WE OBSERVED THAT SEVERAL GENES INVOLVED IN THE LEVODOPA-INDUCED DYSKINESIA UNDERWENT METHYLATION CHANGES. FURTHERMORE, THE RILUZOLE CO-TREATMENT, WHICH IMPROVED THE PHENOTYPE, PINPOINTED SPECIFIC METHYLATION TARGETS, WITH A MORE THAN 20% METHYLATION DIFFERENCE RELATIVE TO LEVODOPA TREATMENT ALONE. THESE FINDINGS INDICATE POTENTIAL NEW DRUGGABLE TARGETS FOR LEVODOPA-INDUCED DYSKINESIA. 2021 3 6425 24 THE TRANSCRIPTION FACTOR REST UP-REGULATES TYROSINE HYDROXYLASE AND ANTIAPOPTOTIC GENES AND PROTECTS DOPAMINERGIC NEURONS AGAINST MANGANESE TOXICITY. DOPAMINERGIC FUNCTIONS ARE IMPORTANT FOR VARIOUS BIOLOGICAL ACTIVITIES, AND THEIR IMPAIRMENT LEADS TO NEURODEGENERATION, A HALLMARK OF PARKINSON'S DISEASE (PD). CHRONIC MANGANESE (MN) EXPOSURE CAUSES THE NEUROLOGICAL DISORDER MANGANISM, PRESENTING SYMPTOMS SIMILAR TO THOSE OF PD. EMERGING EVIDENCE HAS LINKED THE TRANSCRIPTION FACTOR RE1-SILENCING TRANSCRIPTION FACTOR (REST) TO PD AND ALSO ALZHEIMER'S DISEASE. BUT REST'S ROLE IN DOPAMINERGIC NEURONS IS UNCLEAR. HERE, WE INVESTIGATED WHETHER REST PROTECTS DOPAMINERGIC NEURONS AGAINST MN-INDUCED TOXICITY AND ENHANCES EXPRESSION OF THE DOPAMINE-SYNTHESIZING ENZYME TYROSINE HYDROXYLASE (TH). WE REPORT THAT REST BINDS TO RE1 CONSENSUS SITES IN THE TH GENE PROMOTER, STIMULATES TH TRANSCRIPTION, AND INCREASES TH MRNA AND PROTEIN LEVELS IN DOPAMINERGIC CELLS. REST BINDING TO THE TH PROMOTER RECRUITED THE EPIGENETIC MODIFIER CAMP-RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300 AND THEREBY UP-REGULATED TH EXPRESSION. REST RELIEVED MN-INDUCED REPRESSION OF TH PROMOTER ACTIVITY, MRNA, AND PROTEIN LEVELS AND ALSO REDUCED MN-INDUCED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS IN DOPAMINERGIC NEURONS. REST REDUCED MN-INDUCED PROINFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN 1BETA (IL-1BETA), IL-6, AND INTERFERON GAMMA. MOREOVER, REST INHIBITED THE MN-INDUCED PROAPOPTOTIC PROTEINS BCL-2-ASSOCIATED X PROTEIN (BAX) AND DEATH-ASSOCIATED PROTEIN 6 (DAXX) AND ATTENUATED AN MN-INDUCED DECREASE IN THE ANTIAPOPTOTIC PROTEINS BCL-2 AND BCL-XL. REST ALSO ENHANCED THE EXPRESSION OF ANTIOXIDANT PROTEINS, INCLUDING CATALASE, NF-E2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE 1 (HO-1). OUR FINDINGS INDICATE THAT REST ACTIVATES TH EXPRESSION AND THEREBY PROTECTS NEURONS AGAINST MN-INDUCED TOXICITY AND NEUROLOGICAL DISORDERS ASSOCIATED WITH DOPAMINERGIC NEURODEGENERATION. 2020 4 2130 18 EPIGENETIC INACTIVATION OF THE AUTOPHAGY-LYSOSOMAL SYSTEM IN APPENDIX IN PARKINSON'S DISEASE. THE GASTROINTESTINAL TRACT MAY BE A SITE OF ORIGIN FOR ALPHA-SYNUCLEIN PATHOLOGY IN IDIOPATHIC PARKINSON'S DISEASE (PD). DISRUPTION OF THE AUTOPHAGY-LYSOSOME PATHWAY (ALP) MAY CONTRIBUTE TO ALPHA-SYNUCLEIN AGGREGATION. HERE WE EXAMINED EPIGENETIC ALTERATIONS IN THE ALP IN THE APPENDIX BY DEEP SEQUENCING DNA METHYLATION AT 521 ALP GENES. WE IDENTIFIED ABERRANT METHYLATION AT 928 CYTOSINES AFFECTING 326 ALP GENES IN THE APPENDIX OF INDIVIDUALS WITH PD AND WIDESPREAD HYPERMETHYLATION THAT IS ALSO SEEN IN THE BRAIN OF INDIVIDUALS WITH PD. IN MICE, WE FIND THAT DNA METHYLATION CHANGES AT ALP GENES INDUCED BY CHRONIC GUT INFLAMMATION ARE GREATLY EXACERBATED BY ALPHA-SYNUCLEIN PATHOLOGY. DNA METHYLATION CHANGES AT ALP GENES INDUCED BY SYNUCLEINOPATHY ARE ASSOCIATED WITH THE ALP ABNORMALITIES OBSERVED IN THE APPENDIX OF INDIVIDUALS WITH PD SPECIFICALLY INVOLVING LYSOSOMAL GENES. OUR WORK IDENTIFIES EPIGENETIC DYSREGULATION OF THE ALP WHICH MAY SUGGEST A POTENTIAL MECHANISM FOR ACCUMULATION OF ALPHA-SYNUCLEIN PATHOLOGY IN IDIOPATHIC PD. 2021 5 5502 26 RGFP109, A HISTONE DEACETYLASE INHIBITOR ATTENUATES L-DOPA-INDUCED DYSKINESIA IN THE MPTP-LESIONED MARMOSET: A PROOF-OF-CONCEPT STUDY. BACKGROUND: L-3,4-DIHYDROXYPHENYLALANINE (L-DOPA)-INDUCED DYSKINESIA (LID) ARE A COMPLICATION OF CHRONIC DOPAMINE REPLACEMENT THERAPY IN PARKINSON'S DISEASE (PD). RECENT STUDIES HAVE SUGGESTED THAT THE MECHANISMS UNDERLYING DEVELOPMENT AND EXPRESSION OF LID IN PD MAY INVOLVE EPIGENETIC CHANGES THAT INCLUDE DEACETYLATION OF STRIATAL HISTONE PROTEINS. WE HYPOTHESISED THAT INHIBITION OF HISTONE DEACETYLASE, THE ENZYME RESPONSIBLE OF HISTONE DEACETYLATION, WOULD ALLEVIATE LID. METHODS: FOUR FEMALE COMMON MARMOSET (CALLITHRIX JACCHUS) WERE RENDERED PARKINSONIAN BY ADMINISTRATION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP). FOLLOWING STABILISATION OF THE PARKINSONIAN PHENOTYPE, MARMOSETS WERE PRIMED TO EXHIBIT DYSKINESIA WITH CHRONIC ADMINISTRATION OF L-DOPA. WE THEN INVESTIGATED THE EFFECTS OF THE BRAIN-PENETRANT HISTONE DEACETYLASE INHIBITOR, RGFP109 (30 MG/KG P.O. ONCE DAILY FOR 6 DAYS), ON LID AND L-DOPA ANTI-PARKINSONIAN EFFICACY. RESULTS: RGFP109 HAD NO ACUTE EFFECTS ON DYSKINESIA AFTER SINGLE OR 6 DAYS ONCE-DAILY TREATMENT (BOTH P > 0.05). HOWEVER, ONE WEEK FOLLOWING CESSATION OF RGFP109, DYSKINESIA AND DURATION OF ON-TIME WITH DISABLING DYSKINESIA WERE REDUCED BY 37% AND 50%, RESPECTIVELY (BOTH P < 0.05), COMPARED TO THAT SEEN PREVIOUSLY WITH L-DOPA ALONE. THERE WAS NO CHANGE IN ANTI-PARKINSONIAN ACTIONS OF, OR ON-TIME DURATION AFFORDED BY, L-DOPA (P > 0.05). CONCLUSIONS: HISTONE DEACETYLATION INHIBITION MAY REPRESENT A NOVEL APPROACH TO REVERSE ESTABLISHED LID IN PD AND IMPROVE QUALITY OF THE ANTI-PARKINSONIAN BENEFIT PROVIDED BY L-DOPA. 2013 6 2350 29 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021 7 665 30 BLOOD TRANSCRIPTOMICS OF DRUG-NAIVE SPORADIC PARKINSON'S DISEASE PATIENTS. BACKGROUND: PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISORDER THAT IS CLINICALLY DEFINED IN TERMS OF MOTOR SYMPTOMS. THESE ARE PRECEDED BY PRODROMAL NON-MOTOR MANIFESTATIONS THAT PROVE THE SYSTEMIC NATURE OF THE DISEASE. IDENTIFYING GENES AND PATHWAYS ALTERED IN LIVING PATIENTS PROVIDE NEW INFORMATION ON THE DIAGNOSIS AND PATHOGENESIS OF SPORADIC PD. METHODS: CHANGES IN GENE EXPRESSION IN THE BLOOD OF 40 SPORADIC PD PATIENTS AND 20 HEALTHY CONTROLS ("DISCOVERY SET") WERE ANALYZED BY TAKING ADVANTAGE OF THE AFFYMETRIX PLATFORM. PATIENTS WERE AT THE ONSET OF MOTOR SYMPTOMS AND BEFORE INITIATING ANY PHARMACOLOGICAL TREATMENT. DATA ANALYSIS WAS PERFORMED BY APPLYING RANKING-PRINCIPAL COMPONENT ANALYSIS, PUMA AND SIGNIFICANCE ANALYSIS OF MICROARRAYS. FUNCTIONAL ANNOTATIONS WERE ASSIGNED USING GO, DAVID, GSEA TO UNVEIL SIGNIFICANT ENRICHED BIOLOGICAL PROCESSES IN THE DIFFERENTIALLY EXPRESSED GENES. THE EXPRESSIONS OF SELECTED GENES WERE VALIDATED USING RT-QPCR AND SAMPLES FROM AN INDEPENDENT COHORT OF 12 PATIENTS AND CONTROLS ("VALIDATION SET"). RESULTS: GENE EXPRESSION PROFILING OF BLOOD SAMPLES DISCRIMINATES PD PATIENTS FROM HEALTHY CONTROLS AND IDENTIFIES DIFFERENTIALLY EXPRESSED GENES IN BLOOD. THE MAJORITY OF THESE ARE ALSO PRESENT IN DOPAMINERGIC NEURONS OF THE SUBSTANTIA NIGRA, THE KEY SITE OF NEURODEGENERATION. TOGETHER WITH NEURONAL APOPTOSIS, LYMPHOCYTE ACTIVATION AND MITOCHONDRIAL DYSFUNCTION, ALREADY FOUND IN PREVIOUS ANALYSIS OF PD BLOOD AND POST-MORTEM BRAINS, WE UNVEILED TRANSCRIPTOME CHANGES ENRICHED IN BIOLOGICAL TERMS RELATED TO EPIGENETIC MODIFICATIONS INCLUDING CHROMATIN REMODELING AND METHYLATION. CANDIDATE TRANSCRIPTS AS CBX5, TCF3, MAN1C1 AND DOCK10 WERE VALIDATED BY RT-QPCR. CONCLUSIONS: OUR DATA SUPPORT THE USE OF BLOOD TRANSCRIPTOMICS TO STUDY NEURODEGENERATIVE DISEASES. IT IDENTIFIES CHANGES IN CRUCIAL COMPONENTS OF CHROMATIN REMODELING AND METHYLATION MACHINERIES AS EARLY EVENTS IN SPORADIC PD SUGGESTING EPIGENETICS AS TARGET FOR THERAPEUTIC INTERVENTION. 2015 8 5165 26 PRECLINICAL RESERPINE MODELS RECAPITULATING MOTOR AND NON-MOTOR FEATURES OF PARKINSON'S DISEASE: ROLES OF EPIGENETIC UPREGULATION OF ALPHA-SYNUCLEIN AND AUTOPHAGY IMPAIRMENT. RESERPINE IS AN EFFECTIVE DRUG FOR THE CLINICAL TREATMENT OF HYPERTENSION. IT ALSO INDUCES PARKINSON'S DISEASE (PD)-LIKE SYMPTOMS IN HUMANS AND ANIMALS POSSIBLE THROUGH THE INHIBITION OF MONOAMINE VESICULAR TRANSPORTERS, THUS DECREASING THE LEVELS OF MONOAMINE NEUROTRANSMITTERS IN THE BRAIN. HOWEVER, THE PRECISE MECHANISMS REMAIN UNCLEAR. HEREIN, WE AIMED TO DEVELOP A PRECLINICAL RESERPINE MODEL RECAPITULATING THE NON-MOTOR AND MOTOR SYMPTOMS OF PD AND INVESTIGATE THE UNDERLYING POTENTIAL CELLULAR MECHANISMS. INCUBATION OF RESERPINE INDUCED APOPTOSIS, LED TO THE ACCUMULATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), LOWERED DNA METHYLATION OF ALPHA-SYNUCLEIN GENE, RESULTED IN ALPHA-SYNUCLEIN PROTEIN DEPOSITION, AND ELEVATED THE RATIO OF LC3-II/LC3-I AND P62 IN CULTURED SH-SY5Y CELLS. FEEDING RESERPINE DOSE-DEPENDENTLY SHORTENED THE LIFESPAN AND CAUSED IMPAIRMENT OF MOTOR FUNCTIONS IN MALE AND FEMALE DROSOPHILA. MOREOVER, LONG-TERM ORAL ADMINISTRATION OF RESERPINE LED TO MULTIPLE MOTOR AND NON-MOTOR SYMPTOMS, INCLUDING CONSTIPATION, PAIN HYPERSENSITIVITY, OLFACTORY IMPAIRMENT, AND DEPRESSION-LIKE BEHAVIORS IN MICE. THE MECHANISTIC STUDIES SHOWED THAT CHRONIC RESERPINE EXPOSURE CAUSED HYPOMETHYLATION OF THE ALPHA-SYNUCLEIN GENE AND UP-REGULATED ITS EXPRESSION AND ELEVATED THE RATIO OF LC3-II/LC3-I AND EXPRESSION OF P62 IN THE SUBSTANTIA NIGRA OF MICE. THUS, WE ESTABLISHED PRECLINICAL ANIMAL MODELS USING RESERPINE TO RECAPITULATE THE MOTOR AND NON-MOTOR SYMPTOMS OF PD. CHRONIC RESERPINE EXPOSURE EPIGENETICALLY ELEVATED THE LEVELS OF ALPHA-SYNUCLEIN EXPRESSION POSSIBLE BY LOWERING THE DNA METHYLATION STATUS AND INDUCING AUTOPHAGIC IMPAIRMENT IN VITRO AND IN VIVO. 2022 9 6347 24 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 10 2732 28 EXPLORING THE EPIGENETIC REGULATED MODULATION OF FIBROBLAST GROWTH FACTOR 21 INVOLVEMENT IN HIGH-FAT DIET ASSOCIATED PARKINSON'S DISEASE IN RATS. IMBALANCE IN BRAIN GLUCOSE METABOLISM AND EPIGENETIC MODULATION DURING THE DISEASE COURSE OF INSULIN RESISTANCE (IR) ASSOCIATED WITH PARKINSON'S DISEASE (PD) RISK REMAINS A PRIME CONCERN. FIBROBLAST GROWTH FACTOR 21 (FGF21), THE METABOLIC HORMONE, IMPROVES INSULIN SENSITIVITY AND ELICITS ANTI-DIABETIC PROPERTIES. CHRONIC STRESS DURING BRAIN IR MAY MODULATE THE FGF21 EXPRESSION AND ITS DYNAMIC RELEASE VIA EPIGENETIC MODIFICATIONS. METFORMIN REGULATES AND INCREASES THE EXPRESSION OF FGF21 WHICH CAN BE MODULATING IN OBESITY, DIABETES, AND IR. HENCE, THIS STUDY WAS DESIGNED TO INVESTIGATE THE FGF21 EXPRESSION MODULATION VIA AN EPIGENETIC MECHANISM IN PD AND WHETHER METFORMIN (MF), AN AUTOPHAGY ACTIVATOR, AND SODIUM BUTYRATE (NAB), A PAN HISTONE DEACETYLASE INHIBITOR, ALONE AND IN COMBINATION, EXERT ANY THERAPEUTIC BENEFIT IN PD PATHOLOGY EXACERBATED BY HIGH-FAT DIET (HFD). OUR RESULTS PORTRAY THAT THE COMBINATION TREATMENT WITH MF AND NAB POTENTIALLY ATTENUATED THE ABNORMAL LIPID PROFILE AND INCREASED MOTOR PERFORMANCE FOR THE RATS FED WITH HFD FOR 8 WEEKS FOLLOWED BY INTRASTRIATAL 6-HYDROXY DOPAMINE ADMINISTRATION. THE ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) ESTIMATIONS OF C-REACTIVE PROTEIN, TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-1 BETA AND 6, AND FGF21 EXHIBITED EXTENSIVE DOWNREGULATION AFTER TREATMENT WITH THE COMBINATION. LASTLY, MRNA, WESTERN BLOT, HISTOLOGICAL, AND CRESYL VIOLET STAINING DEPICTED THAT THE COMBINATION TREATMENT CAN RESTORE DEGENERATED NEURONAL DENSITY AND INCREASE THE PROTEIN LEVEL COMPARED TO THE DISEASE GROUP. THE FINDINGS FROM THE STUDY EFFECTIVELY CONCLUDE THAT THE EPIGENETIC MECHANISM INVOLVED IN FGF21 MEDIATED FUNCTIONAL ABNORMALITIES IN IR-LINKED PD PATHOLOGY. HENCE, COMBINED TREATMENT WITH MF AND NAB MAY PROVE TO BE A NOVEL COMBINATION IN AMELIORATING IR-ASSOCIATED PD IN RATS, PROBABLY VIA THE UPREGULATION OF FGF21 EXPRESSION. 2023 11 4136 33 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 12 5143 25 POTENTIAL ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY. MANGANESE IS A VITAL NUTRIENT AND IS MAINTAINED AT AN OPTIMAL LEVEL (2.5-5 MG/DAY) IN HUMAN BODY. CHRONIC EXPOSURE TO MANGANESE IS ASSOCIATED WITH NEUROTOXICITY AND CORRELATED WITH THE DEVELOPMENT OF VARIOUS NEUROLOGICAL DISORDERS SUCH AS PARKINSON'S DISEASE. OXIDATIVE STRESS MEDIATED APOPTOTIC CELL DEATH HAS BEEN WELL ESTABLISHED MECHANISM IN MANGANESE INDUCED TOXICITY. OXIDATIVE STRESS HAS A POTENTIAL TO ALTER THE EPIGENETIC MECHANISM OF GENE REGULATION. EPIGENETIC INSIGHT OF MANGANESE NEUROTOXICITY IN CONTEXT OF ITS CORRELATION WITH THE DEVELOPMENT OF PARKINSONISM IS POORLY UNDERSTOOD. PARKINSON'S DISEASE IS CHARACTERIZED BY THE ALPHA-SYNUCLEIN AGGREGATION IN THE FORM OF LEWY BODIES IN NEURONAL CELLS. RECENT FINDINGS ILLUSTRATE THAT MANGANESE CAN CAUSE OVEREXPRESSION OF ALPHA-SYNUCLEIN. ALPHA-SYNUCLEIN ACTS EPIGENETICALLY VIA INTERACTION WITH HISTONE PROTEINS IN REGULATING APOPTOSIS. ALPHA-SYNUCLEIN ALSO CAUSES GLOBAL DNA HYPOMETHYLATION THROUGH SEQUESTRATION OF DNA METHYLTRANSFERASE IN CYTOPLASM. AN INDIVIDUAL GENETIC DIFFERENCE MAY ALSO HAVE AN INFLUENCE ON EPIGENETIC SUSCEPTIBILITY TO MANGANESE NEUROTOXICITY AND THE DEVELOPMENT OF PARKINSON'S DISEASE. THIS REVIEW PRESENTS THE CURRENT STATE OF FINDINGS IN RELATION TO ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY, WITH A SPECIAL EMPHASIS ON THE DEVELOPMENT OF PARKINSON'S DISEASE. 2016 13 135 25 ABERRANT CPG METHYLATION MEDIATES ABNORMAL TRANSCRIPTION OF MAO-A INDUCED BY ACUTE AND CHRONIC L-3,4-DIHYDROXYPHENYLALANINE ADMINISTRATION IN SH-SY5Y NEURONAL CELLS. L-3,4-DIHYDROXYPHENYLALANINE (L-DOPA) REMAINS THE MOST EFFECTIVE DRUG FOR THERAPY OF PARKINSON'S DISEASE (PD); HOWEVER, LONG-TERM USE OF IT CAUSES SERIOUS SIDE EFFECTS. L-DOPA-INDUCED DYSKINESIA (LID) HAS CONSISTENTLY BEEN RELATED TO L-DOPA-DERIVED EXCESSIVE DOPAMINE RELEASE, BUT THE MECHANISMS HAVE NOT BEEN ADDRESSED VERY CLEAR. MONOAMINE OXIDASE A (MAO-A) IS ONE OF THE KEY ENZYMES IN DOPAMINE METABOLISM AND THEREFORE MAY BE INVOLVED IN L-DOPA-INDUCED SIDE EFFECTS. AND, EPIGENETIC MODIFICATION CONTROLS MAO-A GENE TRANSCRIPTION. TO INVESTIGATE THE EFFECTS OF L-DOPA ON MAO-A TRANSCRIPTION AND ITS UNDERLYING EPIGENETIC MECHANISM, NEURONAL SH-SY5Y CELLS WERE TREATED WITH L-DOPA FOR 24 H (ACUTE) AND FOR 7-21 DAYS (CHRONIC). RESULTS SHOWED THAT CHRONIC L-DOPA ADMINISTRATION RESULTED IN A DOSE-DEPENDENT AND TIME-DEPENDENT DOWNREGULATION OF MAO-A, WHEREAS ACUTE L-DOPA ADMINISTRATION INDUCED UPREGULATION OF MAO-A TRANSCRIPTION AND EXPRESSION. MEANWHILE, CHRONIC L-DOPA EXPOSURE INDUCED CPG HYPERMETHYLATION IN MAO-A PROMOTER, WHILE ACUTE L-DOPA ADMINISTRATION CAUSED CPG HYPOMETHYLATION. AND, CPG DEMETHYLATION RESULTED IN REACTIVATION OF MAO-A TRANSCRIPTION. THESE RESULTS INDICATED THAT ABERRANT CPG METHYLATION MIGHT PLAY A KEY ROLE IN MAO-A TRANSCRIPTIONAL MISREGULATION IN L-DOPA ADMINISTRATION. IN ADDITION, RESULTS SHOWED THAT ACUTE L-DOPA ADMINISTRATION INDUCED DOWNREGULATION OF DNA METHYLTRANSFERASE 3A (DNMT3A). TRANSCRIPTION OF TEN-ELEVEN TRANSLOCATION 1 (TET1) WERE SIGNIFICANTLY DOWNREGULATED IN CHRONIC L-DOPA ADMINISTRATION. THESE DATA INDICATED THAT IN CHRONIC L-DOPA ADMINISTRATION, TET1 DOWNREGULATION MIGHT MEDIATE CPG HYPERMETHYLATION, WHICH IS RESPONSIBLE FOR THE DOWNREGULATION OF MAO-A TRANSCRIPTION. IN CONTRAST, IN ACUTE L-DOPA ADMINISTRATION, DNMT3A DOWNREGULATION MIGHT MEDIATE HYPOMETHYLATION, CONTRIBUTING TO THE MAO-A UPREGULATION. IN CONCLUSION, OUR FINDINGS SUGGESTED THAT TET1 AND DNMTS MIGHT MEDIATE ABERRANT CPG METHYLATION, ASSOCIATED WITH THE MISREGULATION OF MAO-A IN L-DOPA ADMINISTRATION, WHICH MIGHT CONTRIBUTE TO DOPAMINE RELEASE ABNORMALLY LEADING TO THE SIDE EFFECTS OF L-DOPA. 2017 14 4927 35 PARKINSON'S DISEASE: FROM PATHOGENESIS TO PHARMACOGENOMICS. PARKINSON'S DISEASE (PD) IS THE SECOND MOST IMPORTANT AGE-RELATED NEURODEGENERATIVE DISORDER IN DEVELOPED SOCIETIES, AFTER ALZHEIMER'S DISEASE, WITH A PREVALENCE RANGING FROM 41 PER 100,000 IN THE FOURTH DECADE OF LIFE TO OVER 1900 PER 100,000 IN PEOPLE OVER 80 YEARS OF AGE. AS A MOVEMENT DISORDER, THE PD PHENOTYPE IS CHARACTERIZED BY RIGIDITY, RESTING TREMOR, AND BRADYKINESIA. PARKINSON'S DISEASE -RELATED NEURODEGENERATION IS LIKELY TO OCCUR SEVERAL DECADES BEFORE THE ONSET OF THE MOTOR SYMPTOMS. POTENTIAL RISK FACTORS INCLUDE ENVIRONMENTAL TOXINS, DRUGS, PESTICIDES, BRAIN MICROTRAUMA, FOCAL CEREBROVASCULAR DAMAGE, AND GENOMIC DEFECTS. PARKINSON'S DISEASE NEUROPATHOLOGY IS CHARACTERIZED BY A SELECTIVE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA PARS COMPACTA, WITH WIDESPREAD INVOLVEMENT OF OTHER CENTRAL NERVOUS SYSTEM (CNS) STRUCTURES AND PERIPHERAL TISSUES. PATHOGENIC MECHANISMS ASSOCIATED WITH GENOMIC, EPIGENETIC AND ENVIRONMENTAL FACTORS LEAD TO CONFORMATIONAL CHANGES AND DEPOSITS OF KEY PROTEINS DUE TO ABNORMALITIES IN THE UBIQUITIN-PROTEASOME SYSTEM TOGETHER WITH DYSREGULATION OF MITOCHONDRIAL FUNCTION AND OXIDATIVE STRESS. CONVENTIONAL PHARMACOLOGICAL TREATMENTS FOR PD ARE DOPAMINE PRECURSORS (LEVODOPA, L-DOPA, L-3,4 DIHIDROXIFENILALANINA), AND OTHER SYMPTOMATIC TREATMENTS INCLUDING DOPAMINE AGONISTS (AMANTADINE, APOMORPHINE, BROMOCRIPTINE, CABERGOLINE, LISURIDE, PERGOLIDE, PRAMIPEXOLE, ROPINIROLE, ROTIGOTINE), MONOAMINE OXIDASE (MAO) INHIBITORS (SELEGILINE, RASAGILINE), AND CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS (ENTACAPONE, TOLCAPONE). THE CHRONIC ADMINISTRATION OF ANTIPARKINSONIAN DRUGS CURRENTLY INDUCES THE "WEARING-OFF PHENOMENON", WITH ADDITIONAL PSYCHOMOTOR AND AUTONOMIC COMPLICATIONS. IN ORDER TO MINIMIZE THESE CLINICAL COMPLICATIONS, NOVEL COMPOUNDS HAVE BEEN DEVELOPED. NOVEL DRUGS AND BIOPRODUCTS FOR THE TREATMENT OF PD SHOULD ADDRESS DOPAMINERGIC NEUROPROTECTION TO REDUCE PREMATURE NEURODEGENERATION IN ADDITION TO ENHANCING DOPAMINERGIC NEUROTRANSMISSION. SINCE BIOCHEMICAL CHANGES AND THERAPEUTIC OUTCOMES ARE HIGHLY DEPENDENT UPON THE GENOMIC PROFILES OF PD PATIENTS, PERSONALIZED TREATMENTS SHOULD RELY ON PHARMACOGENETIC PROCEDURES TO OPTIMIZE THERAPEUTICS. 2017 15 6141 30 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323. 2020 16 6432 27 THE VICIOUS CIRCLE BETWEEN HOMOCYSTEINE, METHYL GROUP-DONATING VITAMINS AND CHRONIC LEVODOPA INTAKE IN PARKINSON'S DISEASE. A BIOMARKER FOR DECLINED METHYLATION CAPACITY IS ELEVATION OF HOMOCYSTEINE LEVELS. THEY INCREASE THE RISK FOR ONSET OF VASCULAR DISEASE AND CONTRIBUTE TO PROGRESSION OF CHRONIC NEURODEGENERATION AND AGING. THIS NARRATIVE REVIEW DISCUSSES ASSOCIATIONS BETWEEN HOMOCYSTEINE, CONSUMPTION OF METHYL GROUP-DONATING VITAMINS AND IMPACT ON DISEASE-GENERATING MECHANISMS IN LEVODOPA-TREATED PATIENTS WITH PARKINSON'S DISEASE. WE CONCLUDE TO RECOMMEND LEVODOPA-TREATED PATIENTS TO SUBSTITUTE THEMSELVES WITH METHYL GROUP-DONATING VITAMINS. THIS IS HARMLESS IN TERMS OF APPLICATION OF FOLIC ACID, METHYLCOBALAMIN OR HYDROXOCOBALAMIN. MOREOVER, WE SUGGEST A CRUCIAL DISCUSSION ON THE VALUE OF THE VARIOUS POPULAR HYPOTHESES ON PARKINSON'S DISEASE-GENERATING MECHANISMS. FINDINGS FROM STUDIES WITH ACUTE LEVODOPA EXPOSURE DESCRIBE OXIDATIVE STRESS GENERATION AND IMPAIRED METHYLATION CAPACITY, WHICH CAUSES GENE DYSFUNCTION. THEIR REPEATED OCCURRENCES CONTRIBUTE TO ONSET OF MITOCHONDRIAL DYSFUNCTION, IRON ENRICHMENT AND PATHOLOGIC PROTEIN ACCUMULATION IN THE LONG TERM. CURRENT RESEARCH UNDERESTIMATES THESE EPIGENETIC, METABOLIC CONSEQUENCES OF CHRONIC LEVODOPA APPLICATION. SUPPLEMENTARY TREATMENT STRATEGIES ARE RECOMMENDED TO AVOID LEVODOPA-RELATED SIDE EFFECTS. 2023 17 6364 30 THE ROLE OF LONG NONCODING RNAS IN NEURODEGENERATIVE DISEASES. LONG NONCODING RNAS (LNCRNAS) ARE TRANSCRIPTS WITH LOW PROTEIN-CODING POTENTIAL BUT OCCUPY A LARGE PART OF TRANSCRIPTIONAL OUTPUT. THEIR ROLES INCLUDE REGULATING GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSCRIPTIONAL LEVEL IN CELLULAR HOMEOSTASIS. HOWEVER, LNCRNA STUDIES ARE STILL IN THEIR INFANCY AND THE FUNCTIONS OF THE VAST MAJORITY OF LNCRNA TRANSCRIPTS REMAIN UNKNOWN. IT IS GENERALLY KNOWN THAT THE FUNCTION OF THE HUMAN NERVOUS SYSTEM LARGELY RELIES ON THE PRECISE REGULATION OF GENE EXPRESSION. VARIOUS STUDIES HAVE SHOWN THAT LNCRNAS HAVE A SIGNIFICANT IMPACT ON NORMAL NEURAL DEVELOPMENT AND ON THE DEVELOPMENT AND PROGRESSION OF NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE FOCUSED ON RECENT STUDIES ASSOCIATED WITH LNCRNAS IN NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), HUNTINGTON'S DISEASE (HD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), MULTIPLE SYSTEM ATROPHY (MSA), FRONTOTEMPORAL LOBAR DEGENERATION (FTLD), AND GLAUCOMA. GLAUCOMA, CAUSED BY UNEXPLAINED GANGLION CELL LESION AND APOPTOSIS, IS NOW LABELED AS A CHRONIC NEURODEGENERATIVE DISORDER [1], AND THEREFORE, WE DISCUSSED THE ASSOCIATION OF LNCRNAS WITH GLAUCOMA AS WELL. WE ILLUSTRATE THE ROLE OF SOME SPECIFIC LNCRNAS, WHICH MAY PROVIDE NEW INSIGHTS INTO OUR UNDERSTANDING OF THE ETIOLOGY AND PATHOPHYSIOLOGY OF THE NEURODEGENERATIVE DISEASES MENTIONED ABOVE. 2017 18 533 27 ASTROCYTIC TRANSCRIPTION FACTOR REST UPREGULATES GLUTAMATE TRANSPORTER EAAT2, PROTECTING DOPAMINERGIC NEURONS FROM MANGANESE-INDUCED EXCITOTOXICITY. CHRONIC EXPOSURE TO HIGH LEVELS OF MANGANESE (MN) LEADS TO MANGANISM, A NEUROLOGICAL DISORDER WITH SIMILAR SYMPTOMS TO THOSE INHERENT TO PARKINSON'S DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF THIS PATHOLOGICAL CONDITION HAVE YET TO BE ESTABLISHED. SINCE THE HUMAN EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) (GLUTAMATE TRANSPORTER 1 IN RODENTS) IS PREDOMINANTLY EXPRESSED IN ASTROCYTES AND ITS DYSREGULATION IS INVOLVED IN MN-INDUCED EXCITOTOXIC NEURONAL INJURY, CHARACTERIZATION OF THE MECHANISMS THAT MEDIATE THE MN-INDUCED IMPAIRMENT IN EAAT2 FUNCTION IS CRUCIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS AGAINST MN NEUROTOXICITY. REPRESSOR ELEMENT 1-SILENCING TRANSCRIPTION FACTOR (REST) EXERTS PROTECTIVE EFFECTS IN MANY NEURODEGENERATIVE DISEASES. BUT THE EFFECTS OF REST ON EAAT2 EXPRESSION AND ENSUING NEUROPROTECTION ARE UNKNOWN. GIVEN THAT THE EAAT2 PROMOTER CONTAINS REST BINDING SITES, THE PRESENT STUDY INVESTIGATED THE ROLE OF REST IN EAAT2 EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN ASTROCYTES AND MN-INDUCED NEUROTOXICITY IN AN ASTROCYTE-NEURON COCULTURE SYSTEM. THE RESULTS REVEAL THAT ASTROCYTIC REST POSITIVELY REGULATES EAAT2 EXPRESSION WITH THE RECRUITMENT OF AN EPIGENETIC MODIFIER, CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300, TO ITS CONSENSUS BINDING SITES IN THE EAAT2 PROMOTER. MOREOVER, ASTROCYTIC OVEREXPRESSION OF REST ATTENUATES MN-INDUCED REDUCTION IN EAAT2 EXPRESSION, LEADING TO ATTENUATION OF GLUTAMATE-INDUCED NEUROTOXICITY IN THE ASTROCYTE-NEURON COCULTURE SYSTEM. OUR FINDINGS DEMONSTRATE THAT ASTROCYTIC REST PLAYS A CRITICAL ROLE IN PROTECTION AGAINST MN-INDUCED NEUROTOXICITY BY ATTENUATING MN-INDUCED EAAT2 REPRESSION AND THE ENSUING EXCITOTOXIC DOPAMINERGIC NEURONAL INJURY. THIS INDICATES THAT ASTROCYTIC REST COULD BE A POTENTIAL MOLECULAR TARGET FOR THE TREATMENT OF MN TOXICITY AND OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH EAAT2 DYSREGULATION. 2021 19 4635 33 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 20 4783 32 NUTRIGENOMICS IN PARKINSON'S DISEASE: DIVERSITY OF MODULATORY ACTIONS OF POLYPHENOLS ON EPIGENETIC EFFECTS INDUCED BY TOXINS. ALTHOUGH THE PATHOGENESIS OF PARKINSON'S DISEASE (PD) IS NOT COMPLETELY UNDERSTOOD, THERE IS A CONSENSUS THAT IT CAN BE CAUSED BY MULTIFACTORIAL MECHANISMS INVOLVING GENETIC SUSCEPTIBILITY, EPIGENETIC MODIFICATIONS INDUCED BY TOXINS AND MITOCHONDRIAL DYSFUNCTION. IN THE PAST 20 YEARS, GREAT EFFORTS HAVE BEEN MADE IN ORDER TO CLARIFY MOLECULAR MECHANISMS THAT ARE RISK FACTORS FOR THIS DISEASE, AS WELL AS TO IDENTIFY BIOACTIVE AGENTS FOR PREVENTION AND SLOWING DOWN OF ITS PROGRESSION. NUTRACEUTICAL PRODUCTS HAVE RECEIVED SUBSTANTIAL INTEREST DUE TO THEIR NUTRITIONAL, SAFE AND THERAPEUTIC EFFECTS ON SEVERAL CHRONIC DISEASES. THE AIM OF THIS REVIEW WAS TO GATHER THE MAIN EVIDENCE OF THE EPIGENETIC MECHANISMS INVOLVED IN THE NEUROPROTECTIVE EFFECTS OF PHENOLIC COMPOUNDS CURRENTLY UNDER INVESTIGATION FOR THE TREATMENT OF TOXIN-INDUCED PD. THESE STUDIES CONFIRM THAT THE NEUROPROTECTIVE ACTIONS OF POLYPHENOLS INVOLVE COMPLEX EPIGENETIC MODULATIONS, DEMONSTRATING THAT THE INTAKE OF THESE NATURAL COMPOUNDS CAN BE A PROMISING, LOW-COST, PHARMACOGENOMIC STRATEGY AGAINST THE DEVELOPMENT OF PD. 2023