論文 - 詳細
| RRC ID | 83338 |
|---|---|
| 著者 | Tsumaki K, Bertens CJF, Nakayama M, Kato S, Jonao Y, Kuribayashi A, Sato K, Ishiyama S, Asakawa M, Aihara R, Yoshioka Y, Homma H, Tanaka H, Fujita K, Okazawa H, Sone M. |
| タイトル | Loss of function of VCP/TER94 causes neurodegeneration. |
| ジャーナル | Dis Model Mech |
| Abstract |
Variants in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function one. To answer this question, we used Drosophila expressing double-stranded RNA against the FTLD-associated gene TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes loss of function. Alterations were also observed in pupal brains and were partially rescued by co-expression of Mcm2, which is involved in control of the cell cycle, suggesting that dysregulation of neuronal proliferation caused the phenotypes. TER94 KD also caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by loss-of-function of VCP. |
| 巻・号 | 17(12) |
| 公開日 | 2024-12-1 |
| DOI | 10.1242/dmm.050359 |
| PII | 364842 |
| PMID | 39629589 |
| PMC | PMC11698056 |
| MeSH | Animals Brain* / metabolism Brain* / pathology Cell Nucleus / metabolism DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster* / genetics Drosophila melanogaster* / metabolism Frontotemporal Lobar Degeneration / genetics Frontotemporal Lobar Degeneration / metabolism Frontotemporal Lobar Degeneration / pathology Gene Knockdown Techniques Humans Loss of Function Mutation / genetics Mushroom Bodies / metabolism Nerve Degeneration / pathology Neurons / metabolism Neurons / pathology Organ Size Phenotype Pupa Valosin Containing Protein* / genetics Valosin Containing Protein* / metabolism |
| IF | 4.651 |
| 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 | News |
| 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 | |
| ショウジョウバエ | GFP-IR-1 |