Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation
β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson’s disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/1721.1/98476 |
| _version_ | 1826213518796390400 |
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| author | Dettmer, Ulf Newman, Andrew J. Soldner, Frank Luth, Eric S. Kim, Nora C. von Saucken, Victoria E. Sanderson, John B. Jaenisch, Rudolf Bartels, Tim Selkoe, Dennis |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Dettmer, Ulf Newman, Andrew J. Soldner, Frank Luth, Eric S. Kim, Nora C. von Saucken, Victoria E. Sanderson, John B. Jaenisch, Rudolf Bartels, Tim Selkoe, Dennis |
| author_sort | Dettmer, Ulf |
| collection | MIT |
| description | β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson’s disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this. |
| first_indexed | 2024-09-23T15:50:31Z |
| format | Article |
| id | mit-1721.1/98476 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:50:31Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/984762022-10-02T04:27:47Z Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation Dettmer, Ulf Newman, Andrew J. Soldner, Frank Luth, Eric S. Kim, Nora C. von Saucken, Victoria E. Sanderson, John B. Jaenisch, Rudolf Bartels, Tim Selkoe, Dennis Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Jaenisch, Rudolf β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson’s disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this. National Institutes of Health (U.S.) (Grant 5R37 CA84198) National Institutes of Health (U.S.) (Grant HD045022) 2015-09-14T13:41:43Z 2015-09-14T13:41:43Z 2015-06 2015-02 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/98476 Dettmer, Ulf, Andrew J. Newman, Frank Soldner, Eric S. Luth, Nora C. Kim, Victoria E. von Saucken, John B. Sanderson, Rudolf Jaenisch, Tim Bartels, and Dennis Selkoe. “Parkinson-Causing α-Synuclein Missense Mutations Shift Native Tetramers to Monomers as a Mechanism for Disease Initiation.” Nature Communications 6 (June 16, 2015): 7314. © 2015 Macmillan Publishers Limited en_US http://dx.doi.org/10.1038/ncomms8314 Nature Communications Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Publishing Group |
| spellingShingle | Dettmer, Ulf Newman, Andrew J. Soldner, Frank Luth, Eric S. Kim, Nora C. von Saucken, Victoria E. Sanderson, John B. Jaenisch, Rudolf Bartels, Tim Selkoe, Dennis Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title_full | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title_fullStr | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title_full_unstemmed | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title_short | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| title_sort | parkinson causing α synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation |
| url | http://hdl.handle.net/1721.1/98476 |
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