1. Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.
- Author
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Ueda, Tetsuhiro, Takeuchi, Toshihide, Fujikake, Nobuhiro, Suzuki, Mari, Minakawa, Eiko N., Ueyama, Morio, Fujino, Yuzo, Kimura, Nobuyuki, Nagano, Seiichi, Yokoseki, Akio, Onodera, Osamu, Mochizuki, Hideki, Mizuno, Toshiki, Wada, Keiji, and Nagai, Yoshitaka
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AMYOTROPHIC lateral sclerosis , *STRESS granules , *MOLECULAR motor proteins , *TDP-43 proteinopathies , *DROSOPHILA , *UBIQUITINATION , *MICROTUBULE-associated proteins - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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