title: Tetraspanin (TSP-17) protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans.
abstract: Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling.
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dow Street, Dundee, United Kingdom.
authors.forename: Neda
authors.initials: N
authors.lastname: Masoudi
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dow Street, Dundee, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Ibanez-Cruceyra
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dow Street, Dundee, United Kingdom.
authors.forename: Sarah-Lena
authors.initials: SL
authors.lastname: Offenburger
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dow Street, Dundee, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dow Street, Dundee, United Kingdom.
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal; D017173:Caenorhabditis elegans / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics*; D018696:Neuroprotective Agents / Q000378:metabolism; D030781:Organisms, Genetically Modified; D016627:Oxidopamine; D017386:Sequence Homology, Amino Acid; D059470:Tetraspanins / Q000235:genetics*
chemical_list: D018696:Neuroprotective Agents; D059470:Tetraspanins; D016627:Oxidopamine