Paraquat-and Rotenone-Induced Models of Parkinson's Disease

Nisticò, Robert; Mehdawy, Bisan; Piccirilli, Silvia; Mercuri, Nicola Biagio

doi:10.1177/039463201102400205

Cited by 95 publications

(58 citation statements)

References 40 publications

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“…In this regard, epidemiological studies have demonstrated that exposure to paraquat, which we have shown redox cycles with sepiapterin reductase, leads to increased risk of Parkinson disease (61). Moreover, neonatal exposure of mice to paraquat results in dopaminergic cell loss and the development of a Parkinson disease phenotype (52). In the lung, altered levels of BH4 can lead to pulmonary hypertension and fibrosis (2).…”

Section: Discussionmentioning

confidence: 94%

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang¹,

Jan

Gray

et al. 2013

Journal of Biological Chemistry

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Background: Enzymes mediating chemical redox cycling in the lung are poorly defined. Results: Sepiapterin reductase was identified as a key mediator of redox cycling and was analyzed using inhibitors and sitedirected mutagenesis. Conclusion: Sepiapterin reductase generates reactive oxygen species during redox cycling in a mechanism distinct from sepiapterin reduction. Significance: This is the first report demonstrating that sepiapterin reductase mediates chemical redox cycling.

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Section: Discussionmentioning

confidence: 94%

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang¹,

Jan

Gray

et al. 2013

Journal of Biological Chemistry

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“…Some studies reveal that certain pesticides (like rotenone) may induce PC-specific symptoms 26,27 . Structurally and functionally, some types of pesticides act like inhibitors of mitochondrial complex I.…”

Section: Discussionmentioning

confidence: 99%

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

Pinhel

Sado

Longo

et al. 2013

Arq. Neuro-Psiquiatr.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder, clinically characterized by bradykinesia, rigidity, resting tremor, and postural instability. Early symptoms of PD are primarily due to the selective degeneration of dopaminergic neurons of the substantia nigra, innervating the neostriatum. The primary cause of PD is unknown, however, mitochondrial failure, oxidative stress and genetic factors, responsible for neurodegeneration in the substantia nigra are investigated hypotheses for the etiology of idiopathic PD 1 . The progression of cell loss is thought to occur over a somewhat protracted period of time in a defined spatiotemporal manner, and the onset of PD symptoms is typically ABSTRACTGenetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. We studied 254 patients with PD and 169 controls. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. We applied the Fisher's exact test and the χ 2 test for statistical analysis (p<0.05). The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls (13%, p=0.014). This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.Key words: Parkinson disease, glutathione transferase, polymorphism genetic, xenobiotics. RESUMOFatores genéticos e ambientais influenciam a patogênese da doença de Parkinson (DP). Variantes genéticas das enzimas glutationa S-transferases (GST) parecem estar envolvidas com a doença. Os objetivos deste estudo foram avaliar a influência de variantes genéticas de GST (GSTT1/GSTM1) e sua associação com exposição a toxinas ambientais em pacientes com DP. Foram estudados 254 pacientes com DP e 169 controles. As variantes para GSTM1/GSTT1 foram analisadas por reação em cadeia da polimerase. Para análise estatística foram aplicados os testes de Fisher e do χ 2 (p<0,05). Tanto a presença quanto a nulidade para GSTT1 e GSTM1 foram semelhantes em pacientes e controles. A nulidade para GSTT1 e GSTM1 (0/0) e contato com agrotóxicos prevaleceu nos pacientes (18%) em relação aos controles (13%, p=0,014). Este estudo sugere associação entre DP e contato prévio com agrotóxicos, cujo efeito parece potencializado em combinação com nulidade para GSTT1/GSTM1. Palavras-Chave: doença de Parkinson, glutationa transferase, polimorfismo genético, xenobióticos.

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“…reserpine, toxic e.g. MPTP [738], rotenone and paraquat [739][740][741][742], and genetic. Despite [748][749][750], Caenorhabditis elegans [492,751] and in mammalians [752] have been developed to study the cellular mechanisms impaired in this disease [746].…”

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Paraquat-and Rotenone-Induced Models of Parkinson's Disease

Cited by 95 publications

References 40 publications

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

The role of α-synuclein in neurodegeneration — An update

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