Gene–environment interactions in sporadic Parkinson's disease

BenMoyal-Segal, Liat; Soreq, Hermona

doi:10.1111/j.1471-4159.2006.03937.x

Cited by 59 publications

(45 citation statements)

References 193 publications

(325 reference statements)

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“…GST detoxified agents are, for example, polycyclic aromatic hydrocarbons, which may be found in pesticides 11 . Therefore, individuals with null genotype for GSTM1 and GSTT1 have a higher risk for oxidative stress associated diseases 12,29 , including PD 10,16 . However, there is little research on this matter, and even less on Brazilian individuals.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that polymorphism in enzymes involved in oxidative metabolism and detoxification could be involved in predisposition to PD. Studies have hypothesized that individuals with poor metabolizing status, based on cytochrome P4502D6 (CYP2D6) genotype could be at risk to PD 9 , though inconsistencies have been reported in the literature 10 . Similarly, polymorphism in enzymes, which generate free radicals or those involved in dopamine neurotransmission such as cytochrome P450 2E1 (CYP2E1), glutathione S-transferases (GST), superoxide dismutase (MnSOD), monoamine oxidase-B (MAO-B), dopamine receptor D2 (DRD2) and dopamine transporter (DAT) which are known to interact with environmental exposures, could be implicated in the pathogenesis of PD 1,11 .…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Examples include Huntington's disease, for which patients with the same polyQ length can exhibit variation in age of disease onset (Wexler et al 2004), Parkinson's disease, in which post-industrial environmental exposures such as insecticides have been correlated with disease onset (Benmoyal-Segal and Soreq 2006), and ALS, in which the majority of the cases are sporadic (Bruijn et al 2004).…”

Section: Small Molecule Effectors Of Neuronal Excitation As Modulatormentioning

confidence: 99%

Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells

Garcia¹,

Casanueva²,

Silva³

et al. 2007

Genes Dev.

103

133

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Protein homeostasis maintains proper intracellular balance by promoting protein folding and clearance mechanisms while minimizing the stress caused by the accumulation of misfolded and damaged proteins. Chronic expression of aggregation-prone proteins is deleterious to the cell and has been linked to a wide range of conformational disorders. The molecular response to misfolded proteins is highly conserved and generally studied as a cell-autonomous process. Here, we provide evidence that neuronal signaling is an important modulator of protein homeostasis in post-synaptic muscle cells. In a forward genetic screen in Caenorhabditis elegans for enhancers of polyglutamine aggregation in muscle cells, we identified unc-30, a neuron-specific transcription factor that regulates the synthesis of the inhibitory neurotransmitter ␥-aminobutyric acid (GABA). We used additional sensors of protein conformational states to show that defective GABA signaling or increased acetylcholine (ACh) signaling causes a general imbalance in protein homeostasis in post-synaptic muscle cells. Moreover, exposure to GABA antagonists or ACh agonists has a similar effect, which reveals that toxins that act at the neuromuscular junction are potent modifiers of protein conformational disorders. These results demonstrate the importance of intercellular communication in intracellular homeostasis.[Keywords: Protein misfolding; polyglutamine aggregation; GABAergic neurons; cholinergic neurons; protein polymorphisms] Supplemental material is available at http://www.genesdev.org.

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“…The majority of cases of PD are idiopathic, likely arising from different combinations of genetic and environmental factors (Benmoyal-Segal and Soreq, 2006). Mutations in the PARK genes lead to rare, familial, mendelian parkinsonism and have provided convergence on cellular processes that might be defective in all PD sufferers (Lesage and Brice, 2009).…”

Section: Ons Cells As a Model For Pdmentioning

confidence: 99%

Disease-specific, neurosphere-derived cells as models for brain disorders

Matigian

Abrahamsen

Sutharsan

et al. 2010

Disease Models &Amp; Mechanisms

181

237

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SUMMARYThere is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.

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Gene–environment interactions in sporadic Parkinson's disease

Abstract: Much has been learned

Cited by 59 publications

References 193 publications

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

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

Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells

Disease-specific, neurosphere-derived cells as models for brain disorders

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