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Principal Investigator: Eunsook Yu Lee
Organization: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
Fiscal Year: 2024
Award: $440,960
Funding agency: National Institute of Environmental Health Sciences
Project Summary
Chronic exposure to high levels of manganese (Mn) causes manganism, a neurological disorder
which shares multiple pathological features with Parkinson's disease (PD). Mn-induced
neurotoxicity includes decreased expression of tyrosine hydroxylase (TH), a rate-limiting enzyme
in dopamine synthesis, and dopaminergic neuronal injury. But the mechanisms of the Mn-induced
neurotoxicity are not completely understood. Estrogenic compounds, such as tamoxifen, a
selective estrogen receptor modulator (SERM), have been shown to be protective in Mn toxicity
and PD, but their mode of action remains to be established. While the transcription factor RE1-
silencing transcription factor (REST) was initially described as a repressor of neuronal genes in
non-neuronal cells during development, it has recently been shown to play a critical role in
protection of adult neurons, and it activates genes that are involved in neuroprotection. Our
preliminary data reveal that Mn decreased REST, whereas TX increased its expression in TH-
expressing neuronal cells. REST protected dopaminergic neurons against Mn neurotoxicity by
attenuating Mn-induced oxidative stress, inflammation and apoptosis. These findings indicate that
REST may mediate TX-induced neuroprotection against Mn toxicity in dopaminergic neurons.
Therefore, investigating the mechanisms of REST in Mn-induced neurotoxicity and TX-induced
protection against Mn toxicity is critical to advance our understanding of Mn neurotoxicity and in
developing therapeutic strategies to treat neurodegenerative diseases associated with
dysfunction of dopaminergic neurons. We hypothesize that REST protects against Mn
neurotoxicity by enhancing expression of TH, as well as the antioxidant/antiapoptotic genes
catalase (CAT) and B-cell lymphoma 2 (Bcl-2), and mediates TX-induced protection against Mn
toxicity via genomic ERα and nongenomic ERα/GPR30 pathways. Our hypothesis will be tested
in the following specific aims: 1) Test if REST in DAergic neurons is protective against Mn
neurotoxicity in mice, 2) Investigate mechanisms of Mn-induced REST reduction and the
protective effects of REST against Mn neurotoxicity via upregulation of TH, CAT and Bcl-2, and
3) Test if DAergic REST is a critical mediator of TX-induced neuroprotection against Mn toxicity.
The outcome of the study will provide critical information on the role of REST in DAergic neuronal
function, Mn toxicity and TX-induced neuroprotection against Mn toxicity. The results also greatly
contribute to the development of `neuroSERMs' to treat NDs associated with DAergic injury, such
as manganism and potentially PD.
Terms: <21+ years old><Adult><Adult Human><Adverse effects><Alzheimer's disease patient><Alzheimer's patient><Animal Disease Models><Antioxidants><Apoptosis><Apoptosis Pathway><Apoptotic><Aquadiol><Attenuated><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Basal Transcription Factor><Basal transcription factor genes><Bcl-2><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Brain><Brain Nervous System><Breast Cancer Patient><Breast Tumor Patient><CMKRL2><CUL-2><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemokine Receptor-Like 2><Chronic><Clinical Research><Clinical Study><Cognitive deficits><DA Neuron><Data><Degenerative Neurologic Disorders><Delta transcription factor><Development><Dimenformon><Diogyn><Diogynets><Disease><Disorder><Dopamine><Dopamine neuron><Dysfunction><ERalpha><ERα><ESR1><ESR1 gene><Encephalon><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogenic Agents><Estrogenic Compounds><Experimental Models><Exposure to><Expression Signature><F-ACT1 protein><Female><Foundations><Functional disorder><G Protein-Coupled Estrogen Receptor><G Protein-Coupled Receptor 30><GPER><GPER gene><GPR30><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genomics><Glia><Glial Cells><Human><Hydroxytyramine><In Vitro><Inflammation><Injury><Intracellular Communication and Signaling><Kolliker's reticulum><Learning><Manganese><Manganese induced parkinsonism><Manganism><Mediating><Mediator><Memory><Mice><Mice Mammals><Mn element><Mn-induced Parkinsonism><Modern Man><Molecular><Molecular Interaction><Molecular Target><Murine><Mus><NF-D nuclear factor><NF-E1 protein><NMP-1 protein><NR3A1><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuronal Dysfunction><Neuronal Injury><Neurons><Neurotoxicity Attenuation><Non-neuronal cell><Nonneuronal cell><Oophorectomy><Outcome Study><Ovariectomy><Ovocyclin><Ovocylin><Oxidative Stress><Oxidative Stress Induction><PRO2286><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathway interactions><Peripheral><Phenotype><Physiopathology><Play><Primary Parkinsonism><Programmed Cell Death><Progynon><RE1-silencing transcription factor><RNA Expression><Repression><Risk Factors><Risk Reduction><Role><SERMs><Selective Estrogen Receptor Modulators><Signal Transduction><Signal Transduction Systems><Signaling><Symptoms><Tamoxifen><Technology><Testing><Therapeutic><Therapeutic Estradiol><Toxic effect><Toxicities><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Tyrosine 3-Monooxygenase><Tyrosine Hydroxylase><UCRBP protein><Up-Regulation><Upregulation><WNT Signaling Pathway><WNT signaling><YY1><YY1 Transcription Factor><YY1 protein><Yin-Yang-1 protein><adulthood><aged><attenuate><attenuates><bcl-2 Genes><beta catenin><biological signal transduction><catalase><ced9 homolog><cognitive defects><combat><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><delta factor><dementia risk><developmental><dopaminergic neuron><epigenetically><estrogenic><female gonadectomy><female sex hormone><gene expression pattern><gene expression signature><in vivo><injuries><insight><life span><lifespan><male><nerve cement><neural dysfunction><neurodegenerative illness><neurological disease><neuron injury><neuron toxicity><neuronal><neuronal toxicity><neuroprotection><neuroprotective><neurotoxicity><nigrostriatal pathway><non-genomic><nongenomic><novel><nuclear matrix protein 1><overexpress><overexpression><pathophysiology><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><pharmacologic><promoter><promotor><protective effect><recruit><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><restoration><risk factor for dementia><risk for dementia><risk-reducing><social role><transcription factor><transcriptional profile><transcriptional signature><vector><yin-yang-1><β-catenin>