論文 - 詳細
| RRC ID | 81469 |
|---|---|
| 著者 | Matsuoka T, Yoshida H, Kasai T, Tozawa T, Iehara T, Chiyonobu T. |
| タイトル | α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies. |
| ジャーナル | Hum Mol Genet |
| Abstract |
Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies. |
| 巻・号 | 33(15) |
| ページ | 1328-1338 |
| 公開日 | 2024-7-22 |
| DOI | 10.1093/hmg/ddae073 |
| PII | 7660708 |
| PMID | 38692286 |
| MeSH | Animals Brain Diseases / genetics Brain Diseases / metabolism Brain Diseases / pathology Disease Models, Animal* Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster* / genetics Haploinsufficiency* / genetics Humans Munc18 Proteins* / genetics Munc18 Proteins* / metabolism Neurodegenerative Diseases / genetics Neurodegenerative Diseases / metabolism Neurodegenerative Diseases / pathology Synucleinopathies / genetics Synucleinopathies / metabolism Synucleinopathies / pathology Trehalose / metabolism alpha-Synuclein* / genetics alpha-Synuclein* / metabolism |
| IF | 5.101 |
| 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 | 5 |
| 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 | |
| ショウジョウバエ | DGRC#107715 |