論文 - 詳細
| RRC ID | 53298 |
|---|---|
| 著者 | Kuwahara T, Inoue K, D'Agati VD, Fujimoto T, Eguchi T, Saha S, Wolozin B, Iwatsubo T, Abeliovich A. |
| タイトル | LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts. |
| ジャーナル | Sci Rep |
| Abstract |
Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson's disease (PD), Crohn's disease, and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models. |
| 巻・号 | 6 |
| ページ | 29945 |
| 公開日 | 2016-7-18 |
| DOI | 10.1038/srep29945 |
| PII | srep29945 |
| PMID | 27424887 |
| PMC | PMC4947924 |
| MeSH | Animals Axons / metabolism* Axons / ultrastructure Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / metabolism* Cell Line Endosomes / metabolism Endosomes / ultrastructure HEK293 Cells Humans Kidney Tubules, Proximal / metabolism Kidney Tubules, Proximal / pathology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / deficiency Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism* Lysosomes / metabolism* Lysosomes / ultrastructure Membrane Proteins / metabolism Mice Motor Neurons / metabolism Protein Binding Protein Serine-Threonine Kinases / metabolism* Protein Transport rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism* |
| IF | 3.998 |
| 引用数 | 44 |
| 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 | 4 |
| 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 | tm1898 |