A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice
Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are n...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/53111 |
| _version_ | 1811236830464442368 |
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| author | Timothy R Sampson Collin Challis Neha Jain Anastasiya Moiseyenko Mark S Ladinsky Gauri G Shastri Taren Thron Brittany D Needham Istvan Horvath Justine W Debelius Stefan Janssen Rob Knight Pernilla Wittung-Stafshede Viviana Gradinaru Matthew Chapman Sarkis K Mazmanian |
| author_facet | Timothy R Sampson Collin Challis Neha Jain Anastasiya Moiseyenko Mark S Ladinsky Gauri G Shastri Taren Thron Brittany D Needham Istvan Horvath Justine W Debelius Stefan Janssen Rob Knight Pernilla Wittung-Stafshede Viviana Gradinaru Matthew Chapman Sarkis K Mazmanian |
| author_sort | Timothy R Sampson |
| collection | DOAJ |
| description | Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain. |
| first_indexed | 2024-04-12T12:14:52Z |
| format | Article |
| id | doaj.art-a828d9d829724627bc449f3bc4f8d4bc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:14:52Z |
| publishDate | 2020-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a828d9d829724627bc449f3bc4f8d4bc2022-12-22T03:33:27ZengeLife Sciences Publications LtdeLife2050-084X2020-02-01910.7554/eLife.53111A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in miceTimothy R Sampson0https://orcid.org/0000-0002-2486-8766Collin Challis1Neha Jain2Anastasiya Moiseyenko3Mark S Ladinsky4Gauri G Shastri5Taren Thron6Brittany D Needham7Istvan Horvath8Justine W Debelius9Stefan Janssen10https://orcid.org/0000-0003-0955-0589Rob Knight11Pernilla Wittung-Stafshede12https://orcid.org/0000-0003-1058-1964Viviana Gradinaru13https://orcid.org/0000-0001-5868-348XMatthew Chapman14Sarkis K Mazmanian15https://orcid.org/0000-0003-2713-1513Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDepartment of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, SwedenDepartment of Pediatrics, University of California, San Diego, San Diego, United StatesDepartment of Pediatrics, University of California, San Diego, San Diego, United StatesDepartment of Pediatrics, University of California, San Diego, San Diego, United States; Department of Computer Science and Engineering, University of California, San Diego, San Diego, United StatesDepartment of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, SwedenDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesDepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United StatesDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, United StatesAmyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.https://elifesciences.org/articles/53111microbiomealpha-synucleinCurli |
| spellingShingle | Timothy R Sampson Collin Challis Neha Jain Anastasiya Moiseyenko Mark S Ladinsky Gauri G Shastri Taren Thron Brittany D Needham Istvan Horvath Justine W Debelius Stefan Janssen Rob Knight Pernilla Wittung-Stafshede Viviana Gradinaru Matthew Chapman Sarkis K Mazmanian A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice eLife microbiome alpha-synuclein Curli |
| title | A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice |
| title_full | A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice |
| title_fullStr | A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice |
| title_full_unstemmed | A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice |
| title_short | A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice |
| title_sort | gut bacterial amyloid promotes α synuclein aggregation and motor impairment in mice |
| topic | microbiome alpha-synuclein Curli |
| url | https://elifesciences.org/articles/53111 |
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