Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Abstract

Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organism Drosophila is an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms in Drosophila that are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, male Drosophila exhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquatinduced oxidative damage. Drosophila mutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production, Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…5B). The sensitivity of ple heterozygous mutant flies to the exposure of 1-octen-3-ol likely reflects the modulatory function of dopamine in the pathways governing survival and locomotory behavior, as seen previously with paraquat exposure (22).…”

“…Pharmacological inhibition of TH, catecholamine uptake, and α-adrenoreceptor antagonists at 1 mM concentration results in failure of viable progeny whereas lower concentration (0.1 mM) significantly delayed the development, indicating the essential function of catecholamines in Drosophila development and viability (50). Drosophila tyrosine hydroxylase is encoded by the pale locus (51), and mutations in the pale gene result in decreased dopamine pools in adult heads, even in the heterozygous state (22). Compared with wild type, ple mutants showed increased susceptibility toward various types of stress, including the dopaminergic toxicant paraquat, indicating that dopamine functions as a key element in the stress response (22,52).…”

“…Drosophila tyrosine hydroxylase is encoded by the pale locus (51), and mutations in the pale gene result in decreased dopamine pools in adult heads, even in the heterozygous state (22). Compared with wild type, ple mutants showed increased susceptibility toward various types of stress, including the dopaminergic toxicant paraquat, indicating that dopamine functions as a key element in the stress response (22,52). Here we also found that 1-octen-3-ol was more toxic in the ple heterozygous mutant lines.…”

“…Considering that 1-octen-3-ol exposure led to alteration of dopamine homeostasis and dopamine neuron loss, we then investigated whether 1-octen-3-ol mediates the variation in the activity of the gene responsible for dopamine biosynthesis, tyrosine hydroxylase (TH), encoded by pale (ple) locus in Drosophila. We exposed two heterozygous loss-of-function mutant strains of the ple gene, ple 2 and ple 4 , known to have mutations in the tyrosine hydroxylase gene and to possess low dopamine pools (22) to 0.5 ppm of 1-octen-3-ol. Heterozygous mutant strains ple 2 and ple 4 exhibited reduced tolerance to 0.5 ppm of 1-octen-3-ol with a 50% mortality obtained at 13.8 and 12.4 d, respectively, compared with wild-type flies exposed to the same concentration of 1-octen-3-ol.…”

Neuroprotective Effect of Decalepis hamiltonii in Paraquat-Induced Neurotoxicity in Drosophila melanogaster: Biochemical and Behavioral Evidences

“…Paraquat (PQ) (1,1-dimethyl-4-4-bipyridynium dichloride) (PQ), is widely used as herbicide. In vivo studies employing Drosophila melanogaster [5], Rattus norvegicus [6] and Mus musculus [7] have revealed that PQ is neurotoxic which affects dopaminergic neurons. The toxicity of PQ is a consequence of generation of ROS mainly hydrogen peroxide and hydroxyl radical [8].…”