The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turno...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2022
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| Online Access: | https://hdl.handle.net/1721.1/146766 |
| _version_ | 1826188456209940480 |
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| author | Hallacli, Erinc Kayatekin, Can Nazeen, Sumaiya Wang, Xiou H Sheinkopf, Zoe Sathyakumar, Shubhangi Sarkar, Souvarish Jiang, Xin Dong, Xianjun Di Maio, Roberto Wang, Wen Keeney, Matthew T Felsky, Daniel Sandoe, Jackson Vahdatshoar, Aazam Udeshi, Namrata D Mani, DR Carr, Steven A Lindquist, Susan De Jager, Philip L Bartel, David P Myers, Chad L Greenamyre, J Timothy Feany, Mel B Sunyaev, Shamil R Chung, Chee Yeun Khurana, Vikram |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hallacli, Erinc Kayatekin, Can Nazeen, Sumaiya Wang, Xiou H Sheinkopf, Zoe Sathyakumar, Shubhangi Sarkar, Souvarish Jiang, Xin Dong, Xianjun Di Maio, Roberto Wang, Wen Keeney, Matthew T Felsky, Daniel Sandoe, Jackson Vahdatshoar, Aazam Udeshi, Namrata D Mani, DR Carr, Steven A Lindquist, Susan De Jager, Philip L Bartel, David P Myers, Chad L Greenamyre, J Timothy Feany, Mel B Sunyaev, Shamil R Chung, Chee Yeun Khurana, Vikram |
| author_sort | Hallacli, Erinc |
| collection | MIT |
| description | Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder. |
| first_indexed | 2024-09-23T07:59:56Z |
| format | Article |
| id | mit-1721.1/146766 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T07:59:56Z |
| publishDate | 2022 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1467662023-07-03T06:22:18Z The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability Hallacli, Erinc Kayatekin, Can Nazeen, Sumaiya Wang, Xiou H Sheinkopf, Zoe Sathyakumar, Shubhangi Sarkar, Souvarish Jiang, Xin Dong, Xianjun Di Maio, Roberto Wang, Wen Keeney, Matthew T Felsky, Daniel Sandoe, Jackson Vahdatshoar, Aazam Udeshi, Namrata D Mani, DR Carr, Steven A Lindquist, Susan De Jager, Philip L Bartel, David P Myers, Chad L Greenamyre, J Timothy Feany, Mel B Sunyaev, Shamil R Chung, Chee Yeun Khurana, Vikram Massachusetts Institute of Technology. Department of Biology Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder. 2022-12-06T18:41:32Z 2022-12-06T18:41:32Z 2022 2022-12-06T18:23:24Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146766 Hallacli, Erinc, Kayatekin, Can, Nazeen, Sumaiya, Wang, Xiou H, Sheinkopf, Zoe et al. 2022. "The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability." Cell, 185 (12). en 10.1016/J.CELL.2022.05.008 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Hallacli, Erinc Kayatekin, Can Nazeen, Sumaiya Wang, Xiou H Sheinkopf, Zoe Sathyakumar, Shubhangi Sarkar, Souvarish Jiang, Xin Dong, Xianjun Di Maio, Roberto Wang, Wen Keeney, Matthew T Felsky, Daniel Sandoe, Jackson Vahdatshoar, Aazam Udeshi, Namrata D Mani, DR Carr, Steven A Lindquist, Susan De Jager, Philip L Bartel, David P Myers, Chad L Greenamyre, J Timothy Feany, Mel B Sunyaev, Shamil R Chung, Chee Yeun Khurana, Vikram The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title | The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title_full | The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title_fullStr | The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title_full_unstemmed | The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title_short | The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability |
| title_sort | parkinson s disease protein alpha synuclein is a modulator of processing bodies and mrna stability |
| url | https://hdl.handle.net/1721.1/146766 |
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