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Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD by 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 is a Medicine article available to read on EtoBox.
What is Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD about?
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 st
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- Author
- 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
- Publisher
- BioMed Central
- Published
- 2024
- Language
- EN
- Field
- Medicine (Health Sciences)