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論文
- タイトル
- タイトル（英）
- Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD
- 参照URL
- https://researchmap.jp/koronku/published_papers/45583220
- 著者
- 著者（英）
- Tetsuhiro Ueda,Toshihide Takeuchi,Nobuhiro Fujikake,Mari Suzuki,Eiko N. Minakawa,Morio Ueyama,Yuzo Fujino,Nobuyuki Kimura,Seiichi Nagano,Akio Yokoseki,Osamu Onodera,Hideki Mochizuki,Toshiki Mizuno,Keiji Wada,Yoshitaka Nagai
- 担当区分
- 概要
- 概要（英）
- Abstract The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.
- 出版者・発行元
- 出版者・発行元（英）
- Springer Science and Business Media LLC
- 誌名
- 誌名（英）
- Acta Neuropathologica Communications
- 巻
- 12
- 号
- 1
- 開始ページ
- 終了ページ
- 出版年月
- 2024年2月4日
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1186/s40478-024-01729-8
- 共同研究・競争的資金等の研究課題
研究者
鈴木 マリ
(スズキ マリ)