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1.
Neurobiol Dis ; 196: 106522, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38705492

RESUMO

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Espécies Reativas de Oxigênio , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Animais , Espécies Reativas de Oxigênio/metabolismo , Ratos , Tricloroetileno/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Rotenona/toxicidade , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Paraquat/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Estresse Oxidativo/efeitos dos fármacos , Humanos , Poluentes Ambientais/toxicidade , Ratos Sprague-Dawley
2.
Mov Disord ; 39(3): 606-613, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38389433

RESUMO

BACKGROUND: Environmental exposure to trichloroethylene (TCE), a carcinogenic dry-cleaning chemical, may be linked to Parkinson's disease (PD). OBJECTIVE: The objective of this study was to determine whether PD and cancer were elevated among attorneys who worked near a contaminated site. METHODS: We surveyed and evaluated attorneys with possible exposure and assessed a comparison group. RESULTS: Seventy-nine of 82 attorneys (96.3%; mean [SD] age: 69.5 [11.4] years; 89.9% men) completed at least one phase of the study. For comparison, 75 lawyers (64.9 [10.2] years; 65.3% men) underwent clinical evaluations. Four (5.1%) of them who worked near the polluted site reported PD, more than expected based on age and sex (1.7%; P = 0.01) but not significantly higher than the comparison group (n = 1 [1.3%]; P = 0.37). Fifteen (19.0%), compared to four in the comparison group (5.3%; P = 0.049), had a TCE-related cancer. CONCLUSIONS: In a retrospective study, diagnoses of PD and TCE-related cancers appeared to be elevated among attorneys who worked next to a contaminated dry-cleaning site. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Neoplasias , Doença de Parkinson , Tricloroetileno , Masculino , Humanos , Idoso , Feminino , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Doença de Parkinson/diagnóstico , Estudos Retrospectivos , Tricloroetileno/análise
3.
J Neurosci ; 41(22): 4937-4947, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33893220

RESUMO

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.SIGNIFICANCE STATEMENT Environmental exposures to pesticides contribute significantly to pathologic processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness, including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone; and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting that VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.


Assuntos
Neurônios Dopaminérgicos/patologia , Degeneração Neural/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Inseticidas/toxicidade , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Endogâmicos Lew , Rotenona/toxicidade
4.
Toxicol Appl Pharmacol ; 451: 116176, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35914559

RESUMO

Microbial alterations within the gut microbiome appear to be a common feature of individuals with Parkinson's disease (PD), providing further evidence for the role of the gut-brain axis in PD development. As a major site of contact with the environment, questions have emerged surrounding the cause and effect of alterations to the gut microbiome by environmental contaminants associated with PD risk, such as pesticides, metals, and organic solvents. Recent data from our lab shows that ingestion of the industrial byproduct and environmental pollutant trichloroethylene (TCE) induces key Parkinsonian pathology within aged rats, including the degeneration of dopaminergic neurons, α-synuclein accumulation, neuroinflammation, and endolysosomal deficits. As TCE is the most common organic contaminant within drinking water, we postulated that ingestion of TCE associated with PD-related neurodegeneration may alter the gut microbiome to a similar extent as observed in persons with PD. To assess this, we collected fecal samples from adult rats treated with 200 mg/kg TCE over 6 weeks via oral gavage - the dose that produced nigrostriatal neurodegeneration - and analyzed the gut microbiome via whole genome shotgun sequencing. Our results showed changes in gut microorganisms reflective of the microbial signatures observed in individuals with idiopathic PD, such as decreased abundance of short-chain fatty acid producing Blautia and elevated lactic-acid producing Bifidobacteria, as well as genera who contain species previously reported as opportunistic pathogens such as Clostridium. From these experimental data, we postulate that TCE exposure within contaminated drinking water could induce alterations of the gut microbiome that contributes to chronic disease risk, including idiopathic PD.


Assuntos
Água Potável , Microbioma Gastrointestinal , Doença de Parkinson , Tricloroetileno , Animais , Ingestão de Alimentos , Doença de Parkinson/etiologia , Ratos , Tricloroetileno/toxicidade
5.
Neurobiol Dis ; 153: 105312, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33636387

RESUMO

Gene-environment interaction is implicated in the majority of idiopathic Parkinson's disease (PD) risk, and some of the most widespread environmental contaminants are selectively toxic to dopaminergic neurons. Pesticides have long been connected to PD incidence, however, it has become increasingly apparent that other industrial byproducts likely influence neurodegeneration. For example, organic solvents, which are used in chemical, machining, and dry-cleaning industries, are of growing concern, as decades of solvent use and their effluence into the environment has contaminated much of the world's groundwater and soil. Like some pesticides, certain organic solvents, such as the chlorinated halocarbon trichloroethylene (TCE), are mitochondrial toxicants, which are collectively implicated in the pathogenesis of dopaminergic neurodegeneration. Recently, we hypothesized a possible gene-environment interaction may occur between environmental mitochondrial toxicants and the protein kinase LRRK2, mutations of which are the most common genetic cause of familial and sporadic PD. In addition, emerging data suggests that elevated wildtype LRRK2 kinase activity also contributes to the pathogenesis of idiopathic PD. To this end, we investigated whether chronic, systemic TCE exposure (200 mg/kg) in aged rats produced wildtype LRRK2 activation and caused nigrostriatal dopaminergic dysfunction. Interestingly, we found that TCE not only induced LRRK2 kinase activity in the brain, but produced a significant dopaminergic lesion in the nigrostriatal tract, elevated oxidative stress, and caused endolysosomal dysfunction and α-synuclein accumulation. Together, these data suggest that TCE-induced LRRK2 kinase activity contributed to the selective toxicity of dopaminergic neurons. We conclude that gene-environment interactions between certain industrial contaminants and LRRK2 likely influence PD risk.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Solventes/toxicidade , Substância Negra/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Interação Gene-Ambiente , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Atividade Motora/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/patologia , Teste de Campo Aberto , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/patologia , Agregados Proteicos/efeitos dos fármacos , Ratos , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo
6.
Neurobiol Dis ; 134: 104626, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31618685

RESUMO

LRRK2 has been implicated in endolysosomal function and likely plays a central role in idiopathic Parkinson's disease (iPD). In iPD, dopaminergic neurons within the substantia nigra are characterized by increased LRRK2 kinase activity, endolysosomal deficits, and accumulation of autophagic vesicles with incompletely degraded substrates, including α-synuclein. Although LRRK2 has been implicated in endolysosomal and autophagic function, it remains unclear whether inhibition of LRRK2 kinase activity can prevent endolysosomal deficits or reduce dopaminergic neurodegeneration. In this study, we characterized the endolysosomal and autophagic defects in surviving dopaminergic neurons of iPD patient brain tissue. We next showed that these defects could be reproduced reliably in vivo using the rotenone model of iPD. Results suggested that there was impaired endosomal maturation, resulting in lysosomal dysfunction and deficits in protein degradation. A highly selective, brain-penetrant LRRK2 kinase inhibitor not only improved apparent endosomal maturation and lysosomal function, but also prevented rotenone-induced neurodegeneration in vivo. The fact that a LRRK2 kinase inhibitor was capable of preventing the neuropathological and endolysosomal abnormalities observed in human iPD suggests that LRRK2 inhibitors may have broad therapeutic utility in iPD, not only in those who carry a LRRK2 mutation.


Assuntos
Neurônios Dopaminérgicos/patologia , Endossomos/patologia , Inibidores Enzimáticos/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Lisossomos/patologia , Doença de Parkinson , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Endossomos/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Masculino , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia
7.
Neurobiol Dis ; 125: 146-153, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30658149

RESUMO

α-Synuclein plays a central role in the pathogenesis of Parkinson's disease (PD); interventions that decrease its expression appear neuroprotective in PD models. Successful translation of these observations into effective therapies will be dependent on the safety of suppressing α-synuclein expression in the adult brain. We investigated long-term α-synuclein knockdown in the adult rat CNS. 8-month old animals received either AAV-sh[Snca] (an RNA interference vector targeting the Snca mRNA transcript) or AAV-sh[Ctrl] (a control vector) unilaterally into the substantia nigra. No signs of systemic toxicity or motor dysfunction were observed in either experimental group over 12 months. Viral transgene expression persisted to 12 months post-inoculation, at which point Snca mRNA expression in substantia nigra dopaminergic neurons of animals that received AAV-sh[Snca] was decreased by ≈90%, and α-synuclein immunoreactivity by >70% relative to the control side. Stereological quantification of Nissl-labeled neurons showed no evidence of neurodegeneration in the substantia nigra 12 months after inoculation with either vector, and we observed abundant dopaminergic neurons with minimal α-synuclein immunoreactivity that appeared otherwise unremarkable in the AAV-sh[Snca] group. Despite the absence of neurodegeneration, some loss of TH expression was evident in nigral neurons after transduction with either vector, presumably a non-specific consequence of vector delivery, cellular transduction, or expression of shRNA or GFP. We conclude that long-term α-synuclein knockdown in the substantia nigra does not cause significant functional deficits in the ascending dopaminergic projection, or neurodegeneration. These findings are encouraging that it may be feasible to target α-synuclein expression therapeutically in PD.


Assuntos
Degeneração Neural/etiologia , Terapêutica com RNAi/métodos , Substância Negra/patologia , alfa-Sinucleína/antagonistas & inibidores , Animais , Dependovirus , Técnicas de Silenciamento de Genes , Vetores Genéticos , Masculino , Interferência de RNA , RNA Interferente Pequeno , Ratos , Ratos Endogâmicos Lew , alfa-Sinucleína/genética
8.
Neurobiol Dis ; 115: 101-114, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29649621

RESUMO

DJ-1 is a redox-sensitive protein with several putative functions important in mitochondrial physiology, protein transcription, proteasome regulation, and chaperone activity. High levels of DJ-1 immunoreactivity are reported in astrocytes surrounding pathology associated with idiopathic Parkinson's disease, possibly reflecting the glial response to oxidative damage. Previous studies showed that astrocytic over-expression of DJ-1 in vitro prevented oxidative stress and mitochondrial dysfunction in primary neurons. Based on these observations, we developed a pseudotyped lentiviral gene transfer vector with specific tropism for CNS astrocytes in vivo to overexpress human DJ-1 protein in astroglial cells. Following vector delivery to the substantia nigra and striatum of adult Lewis rats, the DJ-1 transgene was expressed robustly and specifically within astrocytes. There was no observable transgene expression in neurons or other glial cell types. Three weeks after vector infusion, animals were exposed to rotenone to induce Parkinson's disease-like pathology, including loss of dopaminergic neurons, accumulation of endogenous α-synuclein, and neuroinflammation. Animals over-expressing hDJ-1 in astrocytes were protected from rotenone-induced neurodegeneration, and displayed a marked reduction in neuronal oxidative stress and microglial activation. In addition, α-synuclein accumulation and phosphorylation were decreased within substantia nigra dopaminergic neurons in DJ-1-transduced animals, and expression of LAMP-2A, a marker of chaperone mediated autophagy, was increased. Together, these data indicate that astrocyte-specific overexpression of hDJ-1 protects neighboring neurons against multiple pathologic features of Parkinson's disease and provides the first direct evidence in vivo of a cell non-autonomous neuroprotective function of astroglial DJ-1.


Assuntos
Astrócitos/metabolismo , Inseticidas/toxicidade , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Proteína Desglicase DJ-1/biossíntese , Rotenona/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Expressão Gênica , Humanos , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Proteína Desglicase DJ-1/genética , Ratos , Ratos Endogâmicos Lew
10.
Mol Pharmacol ; 87(6): 1021-34, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25858541

RESUMO

NR4A family orphan nuclear receptors are an important class of transcription factors for development and homeostasis of dopaminergic neurons that also inhibit expression of inflammatory genes in glial cells. The identification of NR4A2 (Nurr1) as a suppressor of nuclear factor κB (NF-κB)-related neuroinflammatory genes in microglia and astrocytes suggests that this receptor could be a target for pharmacologic intervention in neurologic disease, but compounds that promote this activity are lacking. Selected diindolylmethane compounds (C-DIMs) have been shown to activate or inactivate nuclear receptors, including Nurr1, in cancer cells and also suppress astrocyte inflammatory signaling in vitro. Based upon these data, we postulated that C-DIM12 [1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane] would suppress inflammatory signaling in microglia by a Nurr1-dependent mechanism. C-DIM12 inhibited lipopolysaccharide (LPS)-induced expression of NF-κB-regulated genes in BV-2 microglia including nitric oxide synthase (NOS2), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2), and the effects were attenuated by Nurr1-RNA interference. Additionally, C-DIM12 decreased NF-κB activation in NF-κB-GFP (green fluorescent protein) reporter cells and enhanced nuclear translocation of Nurr1 primary microglia. Chromatin immunoprecipitation assays indicated that C-DIM12 decreased lipopolysaccharide-induced p65 binding to the NOS2 promoter and concurrently enhanced binding of Nurr1 to the p65-binding site. Consistent with these findings, C-DIM12 also stabilized binding of the Corepressor for Repressor Element 1 Silencing Transcription Factor (CoREST) and the Nuclear Receptor Corepressor 2 (NCOR2). Collectively, these data identify C-DIM12 as a modulator of Nurr1 activity that results in inhibition of NF-κB-dependent gene expression in glial cells by stabilizing nuclear corepressor proteins, which reduces binding of p65 to inflammatory gene promoters.


Assuntos
Indóis/farmacologia , Microglia/efeitos dos fármacos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Linhagem Celular , Proteínas Correpressoras , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/imunologia , Microglia/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Regiões Promotoras Genéticas , Transporte Proteico , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator de Transcrição RelA/metabolismo , Transcrição Gênica
11.
J Parkinsons Dis ; 14(3): 363-381, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38607765

RESUMO

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal -prevention.


Assuntos
Exposição Ambiental , Doença de Parkinson , Humanos , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/etiologia , Exposição Ambiental/efeitos adversos , Encéfalo/patologia , Encéfalo/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , alfa-Sinucleína/metabolismo
12.
Sci Transl Med ; 16(767): eadl3438, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39356746

RESUMO

Oxidative stress has long been implicated in Parkinson's disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants reportedly mitigate LRRK2 toxicity. Here, using CRISPR-Cas9 gene-edited HEK293 cells, RAW264.7 macrophages, rat primary ventral midbrain cultures, and PD patient-derived lymphoblastoid cells, we found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation and that this was blocked by inhibitors of either LRRK2 kinase or NADPH oxidase 2 (NOX2). Oxidative stress induced by the pesticide rotenone was ameliorated by LRRK2 kinase inhibition and was absent in cells devoid of LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation normally seen in nigral dopaminergic neurons in this model. Mechanistically, LRRK2 kinase activity was shown to regulate phosphorylation of serine-345 in the p47phox subunit of NOX2. This, in turn, led to translocation of p47phox from the cytosol to the membrane-associated gp91phox (NOX2) subunit, activation of the NOX2 enzyme complex, and production of ROS. Thus, LRRK2 kinase activity may drive cellular ROS production in PD through the regulation of NOX2 activity.


Assuntos
Modelos Animais de Doenças , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , NADPH Oxidase 2 , Estresse Oxidativo , Doença de Parkinson , Espécies Reativas de Oxigênio , Rotenona , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/genética , Células HEK293 , Estresse Oxidativo/efeitos dos fármacos , Camundongos , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , Rotenona/farmacologia , Ratos , Peroxidação de Lipídeos , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Ratos Sprague-Dawley , NADPH Oxidases
13.
J Pharmacol Exp Ther ; 345(1): 125-38, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23318470

RESUMO

There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Indóis/farmacocinética , Indóis/uso terapêutico , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Administração Oral , Animais , Anti-Inflamatórios/química , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Indóis/química , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Espectrometria de Massas em Tandem
14.
Toxicol Sci ; 196(2): 218-228, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37669148

RESUMO

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic compound (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.


Assuntos
Doença de Parkinson , Tricloroetileno , Ratos , Camundongos , Masculino , Feminino , Humanos , Animais , Lactente , Tricloroetileno/toxicidade , Roedores , Exposição por Inalação/efeitos adversos , Ratos Endogâmicos Lew , Camundongos Endogâmicos C57BL , Neurônios Dopaminérgicos
15.
bioRxiv ; 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37502893

RESUMO

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic contaminant (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.

16.
J Parkinsons Dis ; 13(2): 203-218, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36938742

RESUMO

The etiologies of Parkinson's disease (PD) remain unclear. Some, such as certain genetic mutations and head trauma, are widely known or easily identified. However, these causes or risk factors do not account for the majority of cases. Other, less visible factors must be at play. Among these is a widely used industrial solvent and common environmental contaminant little recognized for its likely role in PD: trichloroethylene (TCE). TCE is a simple, six-atom molecule that can decaffeinate coffee, degrease metal parts, and dry clean clothes. The colorless chemical was first linked to parkinsonism in 1969. Since then, four case studies involving eight individuals have linked occupational exposure to TCE to PD. In addition, a small epidemiological study found that occupational or hobby exposure to the solvent was associated with a 500% increased risk of developing PD. In multiple animal studies, the chemical reproduces the pathological features of PD.Exposure is not confined to those who work with the chemical. TCE pollutes outdoor air, taints groundwater, and contaminates indoor air. The molecule, like radon, evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected. Despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited. Here, through a literature review and seven illustrative cases, we postulate that this ubiquitous chemical is contributing to the global rise of PD and that TCE is one of its invisible and highly preventable causes. Further research is now necessary to examine this hypothesis.


Assuntos
Doença de Parkinson , Tricloroetileno , Animais , Tricloroetileno/toxicidade , Tricloroetileno/análise , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Solventes/toxicidade , Fatores de Risco
17.
bioRxiv ; 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37873436

RESUMO

Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1ß as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

18.
Curr Environ Health Rep ; 9(4): 563-573, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36201109

RESUMO

PURPOSE OF REVIEW: Sex dimorphism in Parkinson's disease (PD) is an ostensible feature of the neurological disorder, particularly as men are 1.5-2 times more likely to develop PD than women. Clinical features of the disease, such as presentation at onset, most prevalent symptoms, and response to treatment, are also affected by sex. Despite these well-known sex differences in PD risk and phenotype, the mechanisms that impart sex dimorphisms in PD remain poorly understood. RECENT FINDINGS: As PD incidence is influenced by environmental factors, an intriguing pattern has recently emerged in research studies suggesting a male-specific vulnerability to dopaminergic neurodegeneration caused by neurotoxicant exposure, with relative protection in females. These new experimental data have uncovered potential mechanisms that provide clues to the source of sex differences in dopaminergic neurodegeneration and other PD pathology such as alpha-synuclein toxicity. In this review, we discuss the emerging evidence of increased male sensitivity to neurodegeneration from environmental exposures. We examine mechanisms underlying dopaminergic neurodegeneration and PD-related pathologies with evidence supporting the roles of estrogen, SRY expression, the vesicular glutamate transporter VGLUT2, and the microbiome as prospective catalysts for male vulnerability. We also highlight the importance of including sex as a biological variable, particularly when evaluating dopaminergic neurotoxicity in the context of PD.


Assuntos
Doença de Parkinson , Feminino , Masculino , Humanos , Doença de Parkinson/etiologia , Caracteres Sexuais , Estudos Prospectivos
19.
Trends Neurosci ; 45(3): 224-236, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34991886

RESUMO

The etiology of idiopathic Parkinson's disease (iPD) is multifactorial, and both genetics and environmental exposures are risk factors. While mutations in leucine-rich repeat kinase-2 (LRRK2) that are associated with increased kinase activity are the most common cause of autosomal dominant PD, the role of LRRK2 in iPD, independent of mutations, remains uncertain. In this review, we discuss how the architecture of LRRK2 influences kinase activation and how enhanced LRRK2 substrate phosphorylation might contribute to pathogenesis. We describe how oxidative stress and endolysosomal dysfunction, both of which occur in iPD, can activate non-mutated LRRK2 to a similar degree as pathogenic mutations. Similarly, environmental toxicants that are linked epidemiologically to iPD risk can also activate LRRK2. In aggregate, current evidence suggests an important role for LRRK2 in iPD.


Assuntos
Doença de Parkinson , Endossomos/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/metabolismo , Mutação/genética , Fosforilação
20.
J Parkinsons Dis ; 12(1): 45-68, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34719434

RESUMO

Fueled by aging populations and continued environmental contamination, the global burden of Parkinson's disease (PD) is increasing. The disease, or more appropriately diseases, have multiple environmental and genetic influences but no approved disease modifying therapy. Additionally, efforts to prevent this debilitating disease have been limited. As numerous environmental contaminants (e.g., pesticides, metals, industrial chemicals) are implicated in PD, disease prevention is possible. To reduce the burden of PD, we have compiled preclinical and clinical research priorities that highlight both disease prediction and primary prevention. Though not exhaustive, the "PD prevention agenda" builds upon many years of research by our colleagues and proposes next steps through the lens of modifiable risk factors. The agenda identifies ten specific areas of further inquiry and considers the funding and policy changes that will be necessary to help prevent the world's fastest growing brain disease.


Assuntos
Doença de Parkinson , Praguicidas , Humanos , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle
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