RRC ID 45798
著者 Masoudi N, Ibanez-Cruceyra P, Offenburger SL, Holmes A, Gartner A.
タイトル Tetraspanin (TSP-17) protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans.
ジャーナル PLoS Genet
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.
巻・号 10(12)
ページ e1004767
公開日 2014-12-1
DOI 10.1371/journal.pgen.1004767
PII PGENETICS-D-14-00087
PMID 25474638
PMC PMC4256090
MeSH Amino Acid Sequence Animals Behavior, Animal Caenorhabditis elegans / genetics Cytoprotection / genetics Dopaminergic Neurons / drug effects* Dopaminergic Neurons / physiology Molecular Sequence Data Nerve Degeneration / chemically induced Nerve Degeneration / genetics* Neuroprotective Agents / metabolism Organisms, Genetically Modified Oxidopamine* Sequence Homology, Amino Acid Tetraspanins / genetics*
IF 5.175
引用数 15
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm4994 tm5169 tm351 tm4995