1 5515 122 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 2 4136 29 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 3 6425 27 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 5143 27 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 5 6432 30 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 6 6153 24 THE FUNCTION OF THE METALS IN REGULATING EPIGENETICS DURING PARKINSON'S DISEASE. PARKINSON'S MEANS PARKINSON'S DISEASE, A CHRONIC DEGENERATIVE DISEASE OF CENTRAL NERVOUS SYSTEM. THE MAIN AREA WHICH IS AFFECTED BY THIS DISEASE IS MOTOR SYSTEM. SINCE IT FIRSTLY FOUNDED BY JAMES PARKINSON IN HIS 1817 PUBLICATION, NOWADAYS, PEOPLE STILL HAVE LOTS OF QUESTIONS ABOUT THIS DISEASE. THIS REVIEW MAINLY SUMMARIZES THE EPIGENETICS OF PARKINSON'S. DNA METHYLATION IS ONE OF THE EPIGENETIC MECHANISMS OF PARKINSON'S. DURING THE DEVELOPMENT OF DISEASE, GLOBAL HYPOMETHYLATION, AND HYPERMETHYLATION HAPPEN IN DIFFERENT AREAS OF PATIENTS. ANOTHER EPIGENETIC MECHANISM IS HISTONE MODIFICATION. PEOPLE BELIEVE THAT SOME METALS CAN INDUCE PARKINSON'S DISEASE BY MODULATING EPIGENETIC MECHANISMS. THIS REVIEW SUMMARIZES THE RELATIONSHIPS BETWEEN DIFFERENT METALS AND PARKINSON'S DISEASE. HOWEVER, THE SPECIFIC ROLES OF MOST METALS IN EPIGENETICS ARE STILL UNKNOWN, WHICH NEED FURTHER RESEARCH. 2020 7 3345 31 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 8 6904 21 [THE ROLE OF ALUMINUM AND LEAD IN THE DEVELOPMENT OF ALZHEIMER'S AND PARKINSON'S DISEASES]. THE ARTICLE SUMMARIZES THE DATA AVAILABLE IN THE LITERATURE ON THE TOXIC EFFECTS OF ALUMINUM AND LEAD ON THE HUMAN BRAIN AND ASSESSES THE RELATIONSHIP OF THESE EFFECTS TO THE ETIOPATHOGENESIS OF THE MOST COMMON NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER'S AND PARKINSON'S DISEASES. THE ACCUMULATION OF IONS OF THESE METALS IN THE BRAIN STRUCTURES LEADS TO CHRONIC INTOXICATION THAT IS MANIFESTED BY THE MORPHOLOGICAL SIGNS THAT ARE TYPICAL FOR ALZHEIMER'S DISEASE, SUCH AS DEPOSITS OF BETA-AMYLOID AND TAU-PROTEIN MAINLY IN THE FRONTAL AND TEMPORAL REGIONS OF THE CORTEX, AND FOR PARKINSON'S DISEASE, SUCH AS DEGENERATION OF DOPAMINE NEURONS IN THE SUBSTANTIA NIGRA AND THEIR ACCUMULATION OF ALPHA-SYNUCLEIN. THE MOST LIKELY FORMS OF PARTICIPATION OF ALUMINUM AND LEAD IONS IN THE MECHANISMS OF NEURODEGENERATION ARE THE REPLACEMENT OF BIVALENT METAL IONS NECESSARY FOR BRAIN FUNCTIONING, OXIDATIVE STRESS INITIATION, EPIGENETIC MODIFICATIONS OF HISTONES, AND INCREASED EXPRESSION OF NONCODING RIBONUCLEIC ACIDS. 2021 9 2350 32 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 10 6227 22 THE LINK OF ORGANOPHOSPHORUS PESTICIDES WITH NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISEASES BASED ON EVIDENCE AND MECHANISMS. ORGANOPHOSPHORUS (OP) COMPOUNDS HAVE BEEN KNOWN AS THE MOST WIDELY USED PESTICIDES DURING THE PAST HALF CENTURY AND THERE HAVE BEEN A HUGE BODY OF LITERATURE REGARDING THEIR ASSOCIATION WITH HUMAN CHRONIC DISEASES. NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISORDERS INCLUDING ALZHEIMER, PARKINSON, AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), AND AUTISM ARE AMONG THE AFFLICTING NEUROLOGICAL DISEASES WHICH OVERSHADOW HUMAN LIFE AND THEIR HIGHER RISK IN RELATION TO OP EXPOSURES HAVE BEEN UNCOVERED BY EPIDEMIOLOGICAL STUDIES. IN ADDITION, EXPERIMENTAL STUDIES EXPLORING THE UNDERLYING MECHANISMS HAVE PROVIDED SOME EVIDENCE FOR INVOLVEMENT OF CHOLINERGIC DEFICIT, OXIDATIVE STRESS, NEURO-INFLAMMATION, AND EPIGENETIC MODIFICATIONS AS THE PROCESSES WHICH ARE COMMON IN THE TOXICITY OF THE OP AND PATHOPHYSIOLOGY OF THE MENTIONED DISEASES. IN ADDITION, GENETIC MUTATIONS AND POLYMORPHISMS OF DIFFERENT VARIANTS OF SOME GENES LIKE PARAOXONASE HAVE BEEN SHOWN TO BE IMPLICATED IN BOTH SUSCEPTIBILITY TO OPS TOXICITY AND NEUROLOGICAL DISEASES. IN THIS ARTICLE, WE REVIEWED THE EPIDEMIOLOGICAL AS WELL AS EXPERIMENTAL STUDIES EVIDENCING THE ASSOCIATION OF EXPOSURE TO OPS AND INCIDENCE OF NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISEASES. 2018 11 6728 28 VOLTAGE-GATED CALCIUM CHANNELS AND PARKINSON'S DISEASE. A COMPLEX INTERACTION OF ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS COMBINE WITH AGEING TO CAUSE THE MOST PREVALENT OF MOVEMENT DISORDERS PARKINSON'S DISEASE. CURRENT PHARMACOLOGICAL TREATMENTS ONLY TACKLE THE SYMPTOMS AND DO NOT STOP PROGRESSION OF THE DISEASE OR REVERSE THE NEURODEGENERATIVE PROCESS. WHILE SOME INCIDENCES OF PARKINSON'S DISEASE ARISE THROUGH HERITABLE GENETIC DEFECTS, THE CAUSE OF THE MAJORITY OF CASES REMAINS UNKNOWN. LIKEWISE, WHY SOME NEURONAL POPULATIONS ARE MORE SUSCEPTIBLE TO NEURODEGENERATION THAN OTHERS IS NOT CLEAR, BUT AS THE MOLECULAR PATHWAYS RESPONSIBLE FOR THE PROCESS OF CELL DEATH ARE UNRAVELLED, IT IS INCREASINGLY APPARENT THAT DISRUPTED CELLULAR ENERGY METABOLISM PLAYS A CENTRAL ROLE. PRECISE CONTROL OF CELLULAR CALCIUM CONCENTRATIONS IS CRUCIAL FOR MAINTENANCE OF ENERGY HOMEOSTASIS. RECENTLY, DIFFERENTIAL CELLULAR EXPRESSION OF NEURONAL VOLTAGE-GATED CALCIUM CHANNEL (CA(V)) ISOFORMS HAS BEEN IMPLICATED IN THE SUSCEPTIBILITY OF VULNERABLE NEURONS TO NEURODEGENERATION IN PARKINSON'S DISEASE. CA(V) CHANNELS ARE ALSO INVOLVED IN THE SYNAPTIC PLASTICITY RESPONSE TO THE DENERVATION THAT OCCURS IN PARKINSON'S DISEASE AND FOLLOWING CHRONIC TREATMENT WITH ANTI-PARKINSONIAN DRUGS. THIS REVIEW WILL EXAMINE THE PUTATIVE ROLE NEURONAL CA(V) CHANNELS HAVE IN THE PATHOGENESIS AND TREATMENT OF PARKINSON'S DISEASE. 2012 12 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 13 533 32 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 14 4130 24 MECHANISMS OF FERROPTOSIS AND EMERGING LINKS TO THE PATHOLOGY OF NEURODEGENERATIVE DISEASES. NEURODEGENERATIVE DISEASES ARE A DIVERSE CLASS OF DISEASES ATTRIBUTED TO CHRONIC PROGRESSIVE NEURONAL DEGENERATION AND SYNAPTIC LOSS IN THE BRAIN AND/OR SPINAL CORD, INCLUDING ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, HUNTINGTON'S DISEASE, AMYOTROPHIC LATERAL SCLEROSIS AND MULTIPLE SCLEROSIS. THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES IS COMPLEX AND DIVERSE, OFTEN INVOLVING MITOCHONDRIAL DYSFUNCTION, NEUROINFLAMMATION, AND EPIGENETIC CHANGES. HOWEVER, THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES HAS NOT BEEN FULLY ELUCIDATED. RECENTLY, ACCUMULATING EVIDENCE REVEALED THAT FERROPTOSIS, A NEWLY DISCOVERED IRON-DEPENDENT AND LIPID PEROXIDATION-DRIVEN TYPE OF PROGRAMMED CELL DEATH, PROVIDES ANOTHER EXPLANATION FOR THE OCCURRENCE AND PROGRESSION OF NEURODEGENERATIVE DISEASES. HERE, WE PROVIDE AN OVERVIEW OF THE PROCESS AND REGULATION MECHANISMS OF FERROPTOSIS, AND SUMMARIZE CURRENT RESEARCH PROGRESSES THAT SUPPORT THE CONTRIBUTION OF FERROPTOSIS TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. A COMPREHENSIVE UNDERSTANDING OF THE EMERGING ROLES OF FERROPTOSIS IN NEURODEGENERATIVE DISEASES WILL SHED LIGHT ON THE DEVELOPMENT OF NOVEL THERAPEUTIC TECHNOLOGIES AND STRATEGIES FOR SLOWING DOWN THE PROGRESSION OF THESE DISEASES. 2022 15 5580 32 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 16 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 17 6364 27 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 4682 24 NEW PATHWAYS IDENTIFY NOVEL DRUG TARGETS FOR THE PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS AN INCURABLE, PROGRESSIVE NEURODEGENERATIVE DISORDER. AD IS A COMPLEX AND MULTIFACTORIAL DISEASE THAT IS RESPONSIBLE FOR 60-80% OF DEMENTIA CASES. AGING, GENETIC FACTORS, AND EPIGENETIC CHANGES ARE THE MAIN RISK FACTORS FOR AD. TWO AGGREGATION-PRONE PROTEINS PLAY A DECISIVE ROLE IN AD PATHOGENESIS: BETA-AMYLOID (ABETA) AND HYPERPHOSPHORYLATED TAU (PTAU). BOTH OF THEM FORM DEPOSITS AND DIFFUSIBLE TOXIC AGGREGATES IN THE BRAIN. THESE PROTEINS ARE THE BIOMARKERS OF AD. DIFFERENT HYPOTHESES HAVE TRIED TO EXPLAIN AD PATHOGENESIS AND SERVED AS PLATFORMS FOR AD DRUG RESEARCH. EXPERIMENTS DEMONSTRATED THAT BOTH ABETA AND PTAU MIGHT START NEURODEGENERATIVE PROCESSES AND ARE NECESSARY FOR COGNITIVE DECLINE. THE TWO PATHOLOGIES ACT IN SYNERGY. INHIBITION OF THE FORMATION OF TOXIC ABETA AND PTAU AGGREGATES HAS BEEN AN OLD DRUG TARGET. RECENTLY, SUCCESSFUL ABETA CLEARANCE BY MONOCLONAL ANTIBODIES HAS RAISED NEW HOPES FOR AD TREATMENTS IF THE DISEASE IS DETECTED AT EARLY STAGES. MORE RECENTLY, NOVEL TARGETS, E.G., IMPROVEMENTS IN AMYLOID CLEARANCE FROM THE BRAIN, APPLICATION OF SMALL HEAT SHOCK PROTEINS (HSPS), MODULATION OF CHRONIC NEUROINFLAMMATION BY DIFFERENT RECEPTOR LIGANDS, MODULATION OF MICROGLIAL PHAGOCYTOSIS, AND INCREASE IN MYELINATION HAVE BEEN REVEALED IN AD RESEARCH. 2023 19 4635 34 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 4646 25 NEUROPATHOLOGICAL MECHANISMS ASSOCIATED WITH PESTICIDES IN ALZHEIMER'S DISEASE. ENVIRONMENTAL TOXICANTS HAVE BEEN IMPLICATED IN NEURODEGENERATIVE DISEASES, AND PESTICIDE EXPOSURE IS A SUSPECTED ENVIRONMENTAL RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). SEVERAL EPIDEMIOLOGICAL ANALYSES HAVE AFFIRMED A LINK BETWEEN PESTICIDES AND INCIDENCE OF SPORADIC AD. MEANWHILE, IN VITRO AND ANIMAL MODELS OF AD HAVE SHED LIGHT ON POTENTIAL NEUROPATHOLOGICAL MECHANISMS. IN THIS PAPER, A PERSPECTIVE ON NEUROPATHOLOGICAL MECHANISMS UNDERLYING PESTICIDES' INDUCTION OF AD IS PROVIDED. PROPOSED MECHANISMS RANGE FROM GENERIC OXIDATIVE STRESS INDUCTION IN NEURONS TO MORE AD-SPECIFIC PROCESSES INVOLVING AMYLOID-BETA (ABETA) AND HYPERPHOSPHORYLATED TAU (P-TAU). MECHANISMS THAT ARE MORE SPECULATIVE OR INDIRECT IN NATURE, INCLUDING SOMATIC MUTATION, EPIGENETIC MODULATION, IMPAIRMENT OF ADULT NEUROGENESIS, AND MICROBIOTA DYSBIOSIS, ARE ALSO DISCUSSED. CHRONIC TOXICITY MECHANISMS OF ENVIRONMENTAL PESTICIDE EXPOSURE CROSSTALKS IN COMPLEX WAYS AND COULD POTENTIALLY BE MUTUALLY ENHANCING, THUS MAKING THE DECIPHERING OF SIMPLISTIC CAUSAL RELATIONSHIPS DIFFICULT. 2020