Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux
(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580824000694 |
| _version_ | 1797226629564465152 |
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| author | Yoshinori Tanaka Lina Kozuma Hirotsugu Hino Kosuke Takeya Masumi Eto |
| author_facet | Yoshinori Tanaka Lina Kozuma Hirotsugu Hino Kosuke Takeya Masumi Eto |
| author_sort | Yoshinori Tanaka |
| collection | DOAJ |
| description | (Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P. |
| first_indexed | 2024-04-24T14:27:57Z |
| format | Article |
| id | doaj.art-6e41ffab52e64792978198969ecabe96 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-04-24T14:27:57Z |
| publishDate | 2024-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-6e41ffab52e64792978198969ecabe962024-04-03T04:26:51ZengElsevierBiochemistry and Biophysics Reports2405-58082024-07-0138101705Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic fluxYoshinori Tanaka0Lina Kozuma1Hirotsugu Hino2Kosuke Takeya3Masumi Eto4Biochemistry Unit, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, Japan; Corresponding author. Biochemistry Unit, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, 794-8555Japan.Biochemistry Unit, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, JapanDivision of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine, Itabashi-ku, Tokyo, JapanBiochemistry Unit, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, JapanBiochemistry Unit, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, Japan(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.http://www.sciencedirect.com/science/article/pii/S2405580824000694AbemaciclibVacuolin-1Autophagic fluxTDP-43PI(3)P |
| spellingShingle | Yoshinori Tanaka Lina Kozuma Hirotsugu Hino Kosuke Takeya Masumi Eto Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux Biochemistry and Biophysics Reports Abemaciclib Vacuolin-1 Autophagic flux TDP-43 PI(3)P |
| title | Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux |
| title_full | Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux |
| title_fullStr | Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux |
| title_full_unstemmed | Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux |
| title_short | Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux |
| title_sort | abemaciclib and vacuolin 1 decrease aggregate prone tdp 43 accumulation by accelerating autophagic flux |
| topic | Abemaciclib Vacuolin-1 Autophagic flux TDP-43 PI(3)P |
| url | http://www.sciencedirect.com/science/article/pii/S2405580824000694 |
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