Of Pesticides and Men: a California Story of Genes and Environment in Parkinson’s Disease

Abstract

At the start of the post-genomics 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, 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) 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.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

“…While genetic risks have been identified, environmental factors and gene-environment interactions likely account for most PD cases (Nalls et al, 2014; Ritz et al, 2016). We provide evidence that the gut microbiota are required for postnatal events that promote hallmark motor deficits in an animal model.…”

“…Physiological functions in affected individuals, such as altered intestinal absorption, reduced gastric motility, or dietary habits, represent factors that may change the microbiome. Epidemiological evidence has linked specific pesticide exposure to the incidence of PD (Ritz et al, 2016), with some pesticides known to impact microbiome configuration (Gao et al, 2016). Given the structure of αSyn and its ability to associate with membranes (Jo et al, 2000), it is tempting to speculate that extracellular αSyn may act as an antimicrobial, similar to recent observations with amyloid beta (Kumar et al, 2016), and shape the PD microbiome.…”

Occupational pesticide use and Parkinson's disease in the Parkinson Environment Gene (PEG) study

“…First, when estimating the effect of occupational pesticide use we adjusted for other sources of pesticide exposure (frequent household use, ambient workplace, ambient residential) or mutually adjusted for occupational use (yes/no) of other types of pesticides (i.e., OPs, OCs, DTCs, paraquat, rotenone, carbamates, triflumizole, captan, and propargite, pesticides for which we have previously seen associations of ambient exposures or frequent household use with PD[10, 11, 16]). Second, we created different exposure categories combining different pesticide exposure measures.…”

“…In our California based case control study of PD,[9, 10] we conducted a detailed historical assessment of active occupational use of pesticides and personal protective equipment (PPE) use which we are reporting on for the very first time, while our previous reports relied on extensive information for other sources of pesticide exposure for this population, specifically, ambient pesticide exposures from agricultural applications at work places and residences and household pesticide use. Here, we present results for primarily farming-related occupational pesticide use self-reported by participants and complemented by information on chemicals from the California pesticide registration system.…”

Estudo dos efeitos da superexpressão da alfa-sinucleína sobre o tráfego mitocondrial e autofagia em leveduras, células SH-SY5Y e neurônios dopaminérgicos derivados de hiPSC de pacientes com doença de Parkinson

“…However, some studies have demonstrated deficits in degradation systems, linked to neurodegeneration. (Ritz et al 2016;Martella et al, 2016Tanner et al, 2014Marques et al, 2011). under normal conditions, where alpha-synuclein is mainly found at the synaptic terminal; (B) during normal aging, where alpha-synuclein can be found spread throughout the neuron; (C) in early onset PD, where alpha-synuclein is prone to aggregate; (D) in case of overexpression of alpha-synuclein,, leading to the spread out of the protein in the synaptic terminal and the soma; (E) when the gene is knocked down, leading to cell death (Benskey et al, 2016).…”