scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Pesticides that inhibit the ubiquitin-proteasome system: Effect measure modification by genetic variation in SKP1 in Parkinson's disease

TL;DR: Evidence that UPS-inhibiting pesticides play a role in the etiology of PD is provided and genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures is suggested.
About: This article is published in Environmental Research.The article was published on 2013-10-01 and is currently open access. It has received 47 citations till now. The article focuses on the topics: Population.

Summary (3 min read)

1. Introduction

  • Parkinson′s disease (PD) is characterized by both motor deficits and non-motor symptoms that significantly impact quality of life for those affected and their caregivers.
  • A hallmark of PD pathology is the cytoplasmic inclusions known as Lewy bodies predominantly composed of alpha-synuclein protein (Spillantini et al., 1997) but also frequently containing ubiquitin, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), synphilin, and parkin proteins among others (Licker et al., 2009).
  • The authors conducted a population-based case-control study of PD based in a highly agricultural region of Central California that provides the unique opportunity to estimate ambient exposure to individual pesticides by combining address data from their subjects and state records of pesticide usage in commercial agriculture.

2.1. Pesticide screen for 26S proteasome inhibition

  • From the list of pesticides to which the study population was potentially exposed (i.e., at least one subject was assigned any exposure between 1974 and 1999 according to their geographical information system computer model described below), the authors selected 28 compounds (see Supplementary materials, Table S1) and screened for their ability to inhibit 26S UPS activity in a cellular model.
  • These compounds were selected to reflect the range of chemical structures of the 106 active ingredients to which subjects were potentially exposed.
  • Pesticides were dissolved in DMSO to a final concentration of 0.025%, with the exception of sulfur which was dissolved in carbon disulfide.
  • An amount of 26S UPS activity was determined by FACS as previously described (Wang et al., 2006).
  • Briefly, neuroblastoma SK-N-MC cells transfected with an EGFP-degron fusion protein and passaged multiple times were exposed to test compounds (2 mL/well) for 48 h prior to FACS analysis (Beckman XL-MCL).

2.2. Subject recruitment for population-based study

  • Of 1167 PD patients identified, 604 did not meet eligibility criteria; 90 could not be examined by their movement disorder specialists; 94 did not meet published criteria for idiopathic PD (Hughes et al., 1992); and 6 withdrew between examination and interview.
  • All subjects completed a telephone interview for collection of demographics, risk factor data, and residential/workplace address histories used in geocoding.
  • Subjects also provided either blood or saliva for DNA.

2.3. Pesticide exposure assessment

  • Ambient exposures to commercially applied pesticides were estimated by a geographic-information-system-based (GIS) computer model previously described in detail (Goldberg et al., 2008; Wang et al., 2011).
  • Briefly, self-reported historical residential and workplace addresses were geocoded and manually resolved.
  • A 26-year average exposure was calculated for the years 1974–1999, restricting their exposure window to the time prior to initial PD diagnosis.
  • Subjects were considered to have “high” ambient exposure to a pesticide if their 26-year average was equal to or greater than the median 26-year average in exposed controls and to have no/low exposure to that pesticide otherwise.
  • Exclusion of subjects with high exposure to any non-index pesticide from analysis of the index pesticide enables the common reference group (subjects with no/low exposure to all UPSinhibiting pesticides) (i) to be consistent across all analyses of all individual UPS inhibiting pesticides and (ii) to contain less exposure misclassification.

2.4. Genetic variant assessment

  • Selection of single nucleotide polymorphism (SNPs) and genotyping methods are described in the Supplementary materials.
  • The authors selected these five SNPs for effect measure modification analyses as well as UCHL1 (rs5030732) because of prior support for its role in PD (Ragland et al., 2009).
  • Additionally, at the time of genotyping not all controls had been enrolled and interviewed, thus only 453 of 563 Caucasian controls contribute to the effect measure modification analyses.

2.6. Statistical analyses

  • For pesticide marginal effects the authors estimated odds ratios (OR) and 95% confidence intervals (95%CI) using unconditional logistic regression.
  • The authors utilized a dominant genetic model for effect measure modification analyses due to small numbers of variant homozygotes for some SNPs; the dominant genetic model will typically produce effect estimates similar to those of the heterozygotes in the logadditive genetic model when the variant homozygotes are rare.
  • P-values presented are unadjusted for the number of tests performed; for multiple testing considerations, the authors performed 14 tests.
  • All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC).

3. Results

  • From among the 28 pesticides screened (see Supplementary materials, Table S1), 26S UPS activity was significantly inhibited by 10 μM exposure to propargite, cyanazine, and both of the tested organochlorines (dieldrin, endosulfan) in addition to the imidazoles benomyl, carbendazim, and triflumizole, but not the imidazole precursor thiophanate-methyl.
  • Of the 11 pesticides that inhibited the UPS in their screen, no subjects in their study population (see Supplementary materials, Table S3) were exposed to any level of ambient carbendazim, only 2 subjects were exposed to any level of ferbam, and 12 subjects were exposed to any level of rotenone.
  • Therefore, these pesticides had too low a prevalence to be evaluated individually.
  • For subjects with high ambient exposure at either residential or workplace address, the authors observed ORs ranging from 1.21 to 2.21 with some confidence intervals excluding the null.

4. Discussion

  • The authors observed an increase in PD risk with high ambient exposures at both residential and workplace addresses for almost all of the UPS-inhibiting pesticides investigated in this study.
  • Approximately 70% of subjects designated as highly exposed to any one UPS-inhibiting pesticide were actually exposed to two or more pesticides (40% were exposed to three or more), thus the authors had limited ability to investigate any single pesticide to the exclusion of others, and their findings cannot attribute causation or even strength of association to any specific pesticide.
  • Prior studies in model systems have observed alterations in UPS activity, either by assessing 20S activity in cell lysates or 26S activity in live cells.
  • While the function of rs2284312 is unknown, prior research suggests that SKP1 may participate in the complex etiology of PD.

Acknowledgments

  • The authors are exceptionally grateful to all study participants, whose generosity made this research possible.
  • The authors thank Dr. Papp (UCLA); Drs. Checkoway and Farin (University of Washington); and Drs. Rotter and Taylor (Cedars-Sinai Medical Center) for genotyping.

Did you find this useful? Give us your feedback

Citations
More filters
Journal ArticleDOI
TL;DR: Some of the methodological challenges involved in assessing the descriptive, prognostic and etiological epidemiological studies of PD are discussed, and their main findings are summarized.

250 citations


Cites background from "Pesticides that inhibit the ubiquit..."

  • ...[155] Rhodes SL, Fitzmaurice AG, Cockburn M, Bronstein JM, Sinsheimer JS, Ritz B....

    [...]

Journal ArticleDOI
TL;DR: Three pesticide exposure measures were developed in a large population-based case–control study of incident PD in central California and established some specificity for pesticides’ neurodegenerative actions and identified genetically susceptible populations.
Abstract: At the start of the postgenomics era, most Parkinson's disease (PD) etiology cannot be explained by our knowledge of genetic or environmental factors alone. For more than a decade, we have explored gene-environment (GxE) interactions possibly responsible for the heterogeneity of genetic as well as environmental results across populations. We developed three pesticide exposure measures (ambient due to agricultural applications, home and garden use, and occupational use) in a large population-based case-control study of incident PD in central California. Specifically, we assessed interactions with genes responsible for pesticide metabolism (PON1); transport across the blood-brain barrier (ABCB1); pesticides interfering with or depending on dopamine transporter activity (DAT/SLC6A3) and dopamine metabolism (ALDH2); impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1); and contributing to immune dysregulation (HLA-DR). These studies established some specificity for pesticides' neurodegenerative actions, contributed biologic plausibility to epidemiologic findings, and identified genetically susceptible populations.

100 citations

Journal ArticleDOI
TL;DR: A comprehensive evaluation of the potential utilization of Calceolaria species as a source of biopesticides is made and the chemical profile of selected members of the Chilean Calceolarsia integrifolia sensu lato complex represents a significant addition to previous studies.

67 citations


Cites background from "Pesticides that inhibit the ubiquit..."

  • ...The aerial parts of these plants are used in Chile and South America for their analgesic, digestive and diuretic properties (Sacchetti et al., 1999), and as antimicrobials for stomach ailments (Sacchetti et al., 1999; Garbarino et al., 2004)....

    [...]

  • ...For this directive it is crucial to bring about a significant reduction in the use of chemical pesticides, not least through the promotion of sustainable alternative solutions such as organic farming and IPM....

    [...]

  • ...As a result, there is increased interest for application of secondary metabolites in IPM, this has prompted the search for new sources of biologically active natural products, with new modes of action (Conner et al., 2000; Eisner et al., 2000; Meinwald, 2001), characteristics that which enhance their value as practical pesticides (Akhtar et al., 2008; González and Estevez-Braun, 1998; Isman, 2006; Valladares et al., 1997)....

    [...]

  • ...At present they are banned or restricted in the majority of industrialized countries, but are still used in Africa, South Asia, Central and South America (Kumar et al., 2005; Selin and Eckley, 2003; Villa et al., 2003; Rhodes et al., 2013)....

    [...]

  • ...It is crucial for this directive to bring about a significant reduction in the use of chemical pesticides, not least through the promotion of sustainable alternative solutions such as organic farming and IPM (Rosner and Markowitz, 2013; Rhodes et al., 2013)....

    [...]

Journal ArticleDOI
TL;DR: Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively.
Abstract: The proteasome system degrades more than 80% of intracellular proteins into small peptides. Accordingly, the proteasome is involved in many essential cellular functions, such as protein quality control, transcription, immune responses, cell signaling, and apoptosis. Moreover, degradation products are loaded onto major histocompatibility class I molecules to communicate the intracellular protein composition to the immune system. The standard 20S proteasome core complex contains three distinct catalytic active sites that are exchanged upon stimulation with inflammatory cytokines to form the so-called immunoproteasome. Immunoproteasomes are constitutively expressed in immune cells and have different proteolytic activities compared with standard proteasomes. They are rapidly induced in parenchymal cells upon intracellular pathogen infection and are crucial for priming effective CD8(+) T-cell-mediated immune responses against infected cells. Beyond shaping these adaptive immune reactions, immunoproteasomes also regulate the function of immune cells by degradation of inflammatory and immune mediators. Accordingly, they emerge as novel regulators of innate immune responses. The recently unraveled impairment of immunoproteasome function by environmental challenges and by genetic variations of immunoproteasome genes might represent a currently underestimated risk factor for the development and progression of lung diseases. In particular, immunoproteasome dysfunction will dampen resolution of infections, thereby promoting exacerbations, may foster autoimmunity in chronic lung diseases, and possibly contributes to immune evasion of tumor cells. Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, however, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively.

55 citations


Cites background from "Pesticides that inhibit the ubiquit..."

  • ...By now it is well established that proteasome function is impaired by environmental insults: it has been demonstrated that pesticides, diesel exhaust, and cigarette smoke decrease proteasome activity (59, 92, 93, 116), but also drugs such as ethanol have been shown to impair proteasome function (21, 28, 86)....

    [...]

Journal ArticleDOI
TL;DR: It is suggested that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system and these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.
Abstract: The contribution of environmental toxicants to the etiology and risk of Parkinson's disease (PD) has been clearly established, with organochlorine insecticides routinely shown to damage the nigrostriatal dopamine pathway. Although PD is generally considered an adult onset disease, it has been postulated that exposure to environmental contaminants or other factors early in life during critical periods of neurodevelopment could alter the dopaminergic circuit and predispose individuals to developing PD. Recent epidemiological evidence has found exposure to the organochlorine insecticide endosulfan to be a risk factor for PD. However, the specific dopaminergic targets or vulnerable developmental time points related to endosulfan exposure have not been investigated. Thus, we sought to investigate dopaminergic neurotoxicity following developmental exposure to endosulfan as well as following an additional challenge with MPTP. Our in vitro findings demonstrate a reduction in SK-N-SH cells and ventral mesencephalic primary cultures after endosulfan treatment. Using an in vivo developmental model, exposure to endosulfan during gestation and lactation caused a reduction in DAT and TH in the striatum of male offspring. These alterations were exacerbated following subsequent treatment with MPTP. In contrast, exposure of adult mice to endosulfan did not elicit dopaminergic damage and did not appear to increase the vulnerability of the dopamine neurons to MPTP. These findings suggest that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system. Furthermore, these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.

47 citations


Cites background from "Pesticides that inhibit the ubiquit..."

  • ...In addition to these compounds, a recent epidemiological study also identified exposure to the organochlorine insecticide, endosulfan, as a risk factor for PD (Rhodes et al., 2013)....

    [...]

  • ...recent epidemiological study also identified exposure to the organochlorine insecticide, endosulfan, as a risk factor for PD (Rhodes et al., 2013)....

    [...]

References
More filters
Journal ArticleDOI
28 Aug 1997-Nature
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.

6,923 citations

Book
01 Jan 2003
TL;DR: It is reported that protein aggregation directly impaired the function of the ubiquitin-proteasome system, suggesting a potential mechanism linking protein aggregation to cellular disregulation and cell death.
Abstract: Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.

1,997 citations


"Pesticides that inhibit the ubiquit..." refers background in this paper

  • ...UPS inhibition was inferred from high fluorescence (FL) corresponding to the level of EGFP-degron fusion protein that was not selectively degraded by the UPS (Bence et al., 2001)....

    [...]

Journal ArticleDOI
26 Jul 1996-Cell
TL;DR: Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle.

1,402 citations


"Pesticides that inhibit the ubiquit..." refers background in this paper

  • ...N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript cullin1-fbox (SCF) protein complexes involved in target identification for ubiquitination and cell cycle regulation (Bai et al., 1996), as well as presynaptic differentiation (Liao et al., 2004)....

    [...]

  • ...The SKP1 protein is a component of the SKP1-cullin1-fbox (SCF) protein complexes involved in target identification for ubiquitination and cell cycle regulation (Bai et al., 1996), as well as presynaptic differentiation (Liao et al....

    [...]

Journal ArticleDOI
TL;DR: Assessment of clinical features of 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease suggests that studies based on consultant diagnosis of PD, using standard diagnostic criteria, will include cases other than PD, thus distorting results from clinical trials and epidemiologic studies.
Abstract: Many authorities have drawn attention to the difficulties in clinically distinguishing Parkinson's disease (PD) from other parkinsonian syndromes. We assessed the clinical features of 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic PD according to their pathologic findings. Seventy-six percent of these cases were confirmed to have PD. By using selected criteria (asymmetrical onset, no atypical features, and no possible etiology for another parkinsonian syndrome) the proportion of true PD cases identified was increased to 93%, but 32% of pathologically confirmed cases were rejected on this basis. These observations suggest that studies based on consultant diagnosis of PD, using standard diagnostic criteria, will include cases other than PD, thus distorting results from clinical trials and epidemiologic studies. The strict use of additional criteria can reduce misdiagnosis but at the cost of excluding genuine PD cases.

1,228 citations

Journal ArticleDOI
TL;DR: It is shown that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for widespread degradation of outer membrane proteins, and remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and a causal link between the UPS and autophagy is revealed.
Abstract: Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.

868 citations


"Pesticides that inhibit the ubiquit..." refers background in this paper

  • ..., 2009) and prevented parkinmediated mitophagy (Chan et al., 2011), suggesting a link between UPS and mitochondrial dysfunction....

    [...]

  • ...…pesticides in PD as down-regulation resulted in increased vulnerability to UPS inhibition (Yang et al., 2007) and UPS inhibition reduced mRNA expression (Koch et al., 2009) and prevented parkin-mediated mitophagy (Chan et al., 2011), suggesting a link between UPS and mitochondrial dysfunction....

    [...]

Frequently Asked Questions (1)
Q1. What are the contributions mentioned in the paper "Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in skp1 in parkinson׳s disease" ?

Their goal in this study was to screen pesticides for proteasome inhibition and investigate ( i ) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and ( ii ) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. The authors recruited idiopathic PD cases ( n1⁄4360 ) and population-based controls ( n1⁄4816 ) from three counties in California with considerable commercial agriculture. Their results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.