Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration
Many neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer’s disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotyp...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Autophagy Reports |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/27694127.2023.2166722 |
| _version_ | 1827818506754719744 |
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| author | Ron Benyair Sai Srinivas Panapakkam Giridharan Pilar Rivero-Ríos Junya Hasegawa Emily Bristow Eeva-Liisa Eskelinen Merav D Shmueli Vered Fishbain-Yoskovitz Yifat Merbl Lisa M Sharkey Henry L. Paulson Phyllis I Hanson Samarjit Patnaik Ismael Al-Ramahi Juan Botas Juan Marugan Lois S. Weisman |
| author_facet | Ron Benyair Sai Srinivas Panapakkam Giridharan Pilar Rivero-Ríos Junya Hasegawa Emily Bristow Eeva-Liisa Eskelinen Merav D Shmueli Vered Fishbain-Yoskovitz Yifat Merbl Lisa M Sharkey Henry L. Paulson Phyllis I Hanson Samarjit Patnaik Ismael Al-Ramahi Juan Botas Juan Marugan Lois S. Weisman |
| author_sort | Ron Benyair |
| collection | DOAJ |
| description | Many neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer’s disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer’s disease, as well as other tauopathies. We find that in untreated cells, Tau and mHTT are degraded via autophagy. Notably, treatment with NCT-504 diverts these proteins to multivesicular bodies (MVB) and the ESCRT pathway. Specifically, NCT-504 causes a proliferation of endolysosomal organelles including MVB, and an enhanced association of mHTT and Tau with endosomes and MVB. Importantly, depletion of proteins that act late in the ESCRT pathway blocked NCT-504 dependent degradation of Tau. Moreover, NCT-504-mediated degradation of Tau occurred in cells where Atg7 is depleted, which indicates that this pathway is independent of canonical autophagy. Together, these studies reveal that upregulation of traffic through an ESCRT-dependent MVB pathway may provide a therapeutic approach for neurodegenerative diseases. Abbreviations: AD: Alzheimer’s disease CLEAR: Coordinated Lysosomal Expression and Regulation HTT: Huntingtin HD: Huntington’s disease MEF: Mouse embryonic fibroblasts HTT: Mutant Huntingtin MVB: Multivesicular bodies TFEB: Transcription factor EB |
| first_indexed | 2024-03-12T00:54:50Z |
| format | Article |
| id | doaj.art-025cf5e3def14b5b85e8e1ea105c7f8c |
| institution | Directory Open Access Journal |
| issn | 2769-4127 |
| language | English |
| last_indexed | 2024-03-12T00:54:50Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj.art-025cf5e3def14b5b85e8e1ea105c7f8c2023-09-14T13:24:40ZengTaylor & Francis GroupAutophagy Reports2769-41272023-12-012110.1080/27694127.2023.21667222166722Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegenerationRon Benyair0Sai Srinivas Panapakkam Giridharan1Pilar Rivero-Ríos2Junya Hasegawa3Emily Bristow4Eeva-Liisa Eskelinen5Merav D Shmueli6Vered Fishbain-Yoskovitz7Yifat Merbl8Lisa M Sharkey9Henry L. Paulson10Phyllis I Hanson11Samarjit Patnaik12Ismael Al-Ramahi13Juan Botas14Juan Marugan15Lois S. Weisman16Cell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganCell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganCell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganCell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganCell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganInstitute of Biomedicine, University of TurkuWeizmann Institute of ScienceWeizmann Institute of ScienceWeizmann Institute of ScienceUniversity of MichiganUniversity of MichiganUniversity of Michigan School of Medicine, 1150 W. Medical Center DriveNational Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center DriveJan and Dan Duncan Neurological Research InstituteJan and Dan Duncan Neurological Research InstituteNational Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center DriveCell and Developmental Biology, University of Michigan, Ann Arbor, United States; Life Sciences Institute, University of MichiganMany neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer’s disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer’s disease, as well as other tauopathies. We find that in untreated cells, Tau and mHTT are degraded via autophagy. Notably, treatment with NCT-504 diverts these proteins to multivesicular bodies (MVB) and the ESCRT pathway. Specifically, NCT-504 causes a proliferation of endolysosomal organelles including MVB, and an enhanced association of mHTT and Tau with endosomes and MVB. Importantly, depletion of proteins that act late in the ESCRT pathway blocked NCT-504 dependent degradation of Tau. Moreover, NCT-504-mediated degradation of Tau occurred in cells where Atg7 is depleted, which indicates that this pathway is independent of canonical autophagy. Together, these studies reveal that upregulation of traffic through an ESCRT-dependent MVB pathway may provide a therapeutic approach for neurodegenerative diseases. Abbreviations: AD: Alzheimer’s disease CLEAR: Coordinated Lysosomal Expression and Regulation HTT: Huntingtin HD: Huntington’s disease MEF: Mouse embryonic fibroblasts HTT: Mutant Huntingtin MVB: Multivesicular bodies TFEB: Transcription factor EBhttp://dx.doi.org/10.1080/27694127.2023.2166722escrthuntingtonhuntingtinmultivesicular bodies (mvb)nct-504neurodegenerationtau |
| spellingShingle | Ron Benyair Sai Srinivas Panapakkam Giridharan Pilar Rivero-Ríos Junya Hasegawa Emily Bristow Eeva-Liisa Eskelinen Merav D Shmueli Vered Fishbain-Yoskovitz Yifat Merbl Lisa M Sharkey Henry L. Paulson Phyllis I Hanson Samarjit Patnaik Ismael Al-Ramahi Juan Botas Juan Marugan Lois S. Weisman Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration Autophagy Reports escrt huntington huntingtin multivesicular bodies (mvb) nct-504 neurodegeneration tau |
| title | Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| title_full | Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| title_fullStr | Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| title_full_unstemmed | Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| title_short | Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| title_sort | upregulation of the escrt pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration |
| topic | escrt huntington huntingtin multivesicular bodies (mvb) nct-504 neurodegeneration tau |
| url | http://dx.doi.org/10.1080/27694127.2023.2166722 |
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