ABSTRACT
Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson's disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10(-7) for gene-smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10(-11) for nicotine-paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10(-10)). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.
Subject(s)
Nicotine/adverse effects , Parkinson Disease/etiology , Smoking/adverse effects , Animals , Dopamine/metabolism , Drosophila , Gene Expression , Gene-Environment Interaction , Genome-Wide Association Study , Humans , Models, Biological , Parkinson Disease/genetics , Parkinson Disease/metabolismABSTRACT
Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.
Subject(s)
Antibodies/administration & dosage , Antibodies/genetics , Cystamine/administration & dosage , Drosophila melanogaster/genetics , Huntington Disease/drug therapy , Models, Genetic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Animals , Animals, Genetically Modified , Antibodies/metabolism , Cystamine/therapeutic use , Disease Models, Animal , Drosophila melanogaster/growth & development , Drug Therapy, Combination , Female , Genetic Therapy/methods , Humans , Huntingtin Protein , Huntington Disease/diet therapy , Huntington Disease/pathology , Male , Nerve Degeneration/diet therapy , Nerve Degeneration/pathology , Nerve Degeneration/prevention & control , Nerve Tissue Proteins/biosynthesis , Nuclear Proteins/biosynthesis , Photoreceptor Cells, Invertebrate/drug effects , Photoreceptor Cells, Invertebrate/pathology , Survival Analysis , Treatment OutcomeABSTRACT
Intracellular antibodies (intrabodies) and the chaperone, heat shock protein 70 (Hsp70), have each shown potential as therapeutics for neurodegenerative diseases in vitro and in vivo. Investigating combinational therapy in an established Drosophila model of Huntington's disease (HD), we show that Hsp70 and intrabody actually affect different aspects of the disease. Overexpression of human Hsp70 resulted in improved survival of HD flies to eclosion and prolonged adult life compared with intrabody treatment alone. An additive effect on adult survival was observed when the two therapies were combined. Intrabody was more successful at suppressing neurodegeneration in photoreceptors than was Hsp70. Furthermore, Hsp70 treatment alone did not block aggregation of mutant huntingtin, a process slowed by intrabody. Expression of each is restricted to the nervous system, which implies different neuronal populations respond distinctly to these treatments. Importantly, a role for endogenous Hsp70 in suppression of mutant huntingtin pathology was confirmed by a separate set of genetic studies in which HD flies deficient for Hsp70 showed significantly increased pathology. We conclude that a combinational approach of intrabody with enhanced Hsp70 expression is beneficial in addressing multiple pathologies associated with HD and has potential application for other neurodegenerative disorders.