論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4994 tm5169 tm351 tm4995 |