Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.

Autor: Ueda T; Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.; Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan., Takeuchi T; Life Science Research Institute, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. takeuchi@med.kindai.ac.jp.; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. takeuchi@med.kindai.ac.jp., Fujikake N; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan., Suzuki M; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan., Minakawa EN; Department of Neurophysiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan., Ueyama M; Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan., Fujino Y; Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.; Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan., Kimura N; Department of Veterinary Associated Science, Faculty of Veterinary Medicine, Okayama University of Science, Ehime, 794-8555, Japan., Nagano S; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.; Department of Neurology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan., Yokoseki A; Department of Neurology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan., Onodera O; Department of Neurology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan., Mochizuki H; Department of Neurology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan., Mizuno T; Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan., Wada K; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan., Nagai Y; Department of Neurology, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. yoshi.nagai@med.kindai.ac.jp.; Life Science Research Institute, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. yoshi.nagai@med.kindai.ac.jp.; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. yoshi.nagai@med.kindai.ac.jp.; Department of Neurology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. yoshi.nagai@med.kindai.ac.jp.; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan. yoshi.nagai@med.kindai.ac.jp.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Feb 04; Vol. 12 (1), pp. 20. Date of Electronic Publication: 2024 Feb 04.
DOI: 10.1186/s40478-024-01729-8
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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