دورية أكاديمية
Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.
العنوان: | Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD. |
---|---|
المؤلفون: | 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. |
المصدر: | Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Feb 04; Vol. 12 (1), pp. 20. Date of Electronic Publication: 2024 Feb 04. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : BioMed Central, [2013]- |
مواضيع طبية MeSH: | Amyotrophic Lateral Sclerosis*/pathology , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/metabolism , Dynactin Complex*/genetics , Frontotemporal Dementia*/pathology , Drosophila Proteins*/genetics, Animals ; Humans ; Drosophila/metabolism ; Stress Granules |
مستخلص: | 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).) |
References: | Hum Mol Genet. 2015 Dec 1;24(23):6675-86. (PMID: 26362253) Neuron. 2003 Sep 25;40(1):25-40. (PMID: 14527431) Neuron. 2002 May 30;34(5):729-41. (PMID: 12062020) Nat Commun. 2017 Oct 11;8(1):861. (PMID: 29021520) J Neurol Sci. 2010 Feb 15;289(1-2):149-54. (PMID: 19732908) Nat Rev Neurosci. 2011 Nov 30;13(1):38-50. (PMID: 22127299) Muscle Nerve. 2009 Jul;40(1):19-31. (PMID: 19533646) Nat Genet. 2003 Apr;33(4):455-6. (PMID: 12627231) PLoS One. 2013;8(2):e54511. (PMID: 23408943) Science. 2021 Jun 25;372(6549):eabc3593. (PMID: 34739326) Structure. 2016 Sep 6;24(9):1537-49. (PMID: 27545621) Parkinsonism Relat Disord. 2009 May;15(4):281-6. (PMID: 18723384) J Cell Biol. 2013 Apr 29;201(3):361-72. (PMID: 23629963) Front Neurosci. 2023 Jun 09;17:1164251. (PMID: 37360176) Neuron. 2013 Aug 7;79(3):416-38. (PMID: 23931993) J Cell Sci. 2009 Nov 1;122(Pt 21):3973-82. (PMID: 19825938) Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11. (PMID: 17084815) Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):5883-5894. (PMID: 32132204) Neuron. 2012 Apr 26;74(2):331-43. (PMID: 22542186) Neuron. 2020 Dec 9;108(5):822-842. (PMID: 32931756) Neuron. 2017 Apr 5;94(1):108-124.e7. (PMID: 28343865) PLoS One. 2011;6(7):e22850. (PMID: 21829535) EBioMedicine. 2017 Jul;21:218-227. (PMID: 28625517) Mol Cell. 2016 Sep 1;63(5):796-810. (PMID: 27570075) Exp Gerontol. 1997 Jul-Oct;32(4-5):441-50. (PMID: 9315448) J Mov Disord. 2021 Jan;14(1):1-9. (PMID: 32942840) NPJ Parkinsons Dis. 2023 Mar 7;9(1):35. (PMID: 36879021) J Neuropathol Exp Neurol. 2007 Feb;66(2):152-7. (PMID: 17279000) Neuron. 2012 Apr 26;74(2):344-60. (PMID: 22542187) Neurosci Lett. 2021 Nov 1;764:136234. (PMID: 34508845) J Cell Sci. 2014 Mar 15;127(Pt 6):1263-78. (PMID: 24424030) Mol Ther Nucleic Acids. 2023 Jan 16;31:353-366. (PMID: 36817728) EMBO J. 2021 Apr 1;40(7):e106177. (PMID: 33694180) Neurosci Lett. 2018 Feb 14;666:98-103. (PMID: 29273399) Nature. 2016 Nov 10;539(7628):197-206. (PMID: 27830784) Nat Rev Neurosci. 2021 Apr;22(4):197-208. (PMID: 33654312) Cell. 2013 Jun 20;153(7):1461-74. (PMID: 23791177) Mol Cell. 2018 Jun 7;70(5):906-919.e7. (PMID: 29804830) Nat Med. 2011 Jul 24;17(8):968-74. (PMID: 21785432) Nat Genet. 2009 Feb;41(2):163-5. (PMID: 19136952) J Neuropathol Exp Neurol. 2017 Aug 1;76(8):676-682. (PMID: 28789478) J Pharmacol Exp Ther. 2003 Apr;305(1):375-84. (PMID: 12649392) J Neuropathol Exp Neurol. 2007 Jul;66(7):617-27. (PMID: 17620987) Neurol Genet. 2021 May 18;7(3):e596. (PMID: 34169147) Science. 2006 Oct 6;314(5796):130-3. (PMID: 17023659) |
معلومات مُعتمدة: | 21H02840 Japan Society for the Promotion of Science; 22H02792 Japan Society for the Promotion of Science; 24659438 Japan Society for the Promotion of Science; 17H05699 Japan Society for the Promotion of Science; 20H05927 Japan Society for the Promotion of Science; 11013026 Japan Society for the Promotion of Science; JP15dm0107026 Japan Agency for Medical Research and Development; JP20dm0107061 Japan Agency for Medical Research and Development; JP16ek0109018 Japan Agency for Medical Research and Development; JP19ek0109222 Japan Agency for Medical Research and Development; JP20ek0109316 Japan Agency for Medical Research and Development; JPMJPR17H8 Precursory Research for Embryonic Science and Technology; RGY0066/2017 Human Frontier Science Program |
فهرسة مساهمة: | Keywords: Aggregation; DCTN1; Microtubule-dependent transport; Stress granule; TDP-43 |
المشرفين على المادة: | 0 (DNA-Binding Proteins) 0 (Dynactin Complex) 0 (TBPH protein, Drosophila) 0 (Drosophila Proteins) |
تواريخ الأحداث: | Date Created: 20240204 Date Completed: 20240206 Latest Revision: 20240307 |
رمز التحديث: | 20240307 |
مُعرف محوري في PubMed: | PMC10840176 |
DOI: | 10.1186/s40478-024-01729-8 |
PMID: | 38311779 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2051-5960 |
---|---|
DOI: | 10.1186/s40478-024-01729-8 |