Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease
The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a si...
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Frontiers Media S.A.
2021-03-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.552549/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michele Perni Annemieke van der Goot Ryan Limbocker Ryan Limbocker Tjakko J. van Ham Francesco A. Aprile Catherine K. Xu Patrick Flagmeier Karen Thijssen Pietro Sormanni Giuliana Fusco Serene W. Chen Pavan K. Challa Julius B. Kirkegaard Romain F. Laine Kai Yu Ma Kai Yu Ma Martin B. D. Müller Martin B. D. Müller Tessa Sinnige Janet R. Kumita Samuel I. A. Cohen Renée Seinstra Gabriele S. Kaminski Schierle Clemens F. Kaminski Denise Barbut Alfonso De Simone Tuomas P. J. Knowles Michael Zasloff Ellen A. A. Nollen Michele Vendruscolo Christopher M. Dobson |
spellingShingle |
Michele Perni Annemieke van der Goot Ryan Limbocker Ryan Limbocker Tjakko J. van Ham Francesco A. Aprile Catherine K. Xu Patrick Flagmeier Karen Thijssen Pietro Sormanni Giuliana Fusco Serene W. Chen Pavan K. Challa Julius B. Kirkegaard Romain F. Laine Kai Yu Ma Kai Yu Ma Martin B. D. Müller Martin B. D. Müller Tessa Sinnige Janet R. Kumita Samuel I. A. Cohen Renée Seinstra Gabriele S. Kaminski Schierle Clemens F. Kaminski Denise Barbut Alfonso De Simone Tuomas P. J. Knowles Michael Zasloff Ellen A. A. Nollen Michele Vendruscolo Christopher M. Dobson Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease Frontiers in Cell and Developmental Biology C. elegans Parkinson's disease alpha-synuclein drug discovery protein aggregation protein misfolding |
author_facet |
Michele Perni Annemieke van der Goot Ryan Limbocker Ryan Limbocker Tjakko J. van Ham Francesco A. Aprile Catherine K. Xu Patrick Flagmeier Karen Thijssen Pietro Sormanni Giuliana Fusco Serene W. Chen Pavan K. Challa Julius B. Kirkegaard Romain F. Laine Kai Yu Ma Kai Yu Ma Martin B. D. Müller Martin B. D. Müller Tessa Sinnige Janet R. Kumita Samuel I. A. Cohen Renée Seinstra Gabriele S. Kaminski Schierle Clemens F. Kaminski Denise Barbut Alfonso De Simone Tuomas P. J. Knowles Michael Zasloff Ellen A. A. Nollen Michele Vendruscolo Christopher M. Dobson |
author_sort |
Michele Perni |
title |
Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease |
title_short |
Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease |
title_full |
Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease |
title_fullStr |
Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease |
title_full_unstemmed |
Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease |
title_sort |
comparative studies in the a30p and a53t α-synuclein c. elegans strains to investigate the molecular origins of parkinson's disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-03-01 |
description |
The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research. |
topic |
C. elegans Parkinson's disease alpha-synuclein drug discovery protein aggregation protein misfolding |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.552549/full |
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doaj-40381e7ca771461e9f79bf4da89520192021-03-22T05:29:30ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-03-01910.3389/fcell.2021.552549552549Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's DiseaseMichele Perni0Annemieke van der Goot1Ryan Limbocker2Ryan Limbocker3Tjakko J. van Ham4Francesco A. Aprile5Catherine K. Xu6Patrick Flagmeier7Karen Thijssen8Pietro Sormanni9Giuliana Fusco10Serene W. Chen11Pavan K. Challa12Julius B. Kirkegaard13Romain F. Laine14Kai Yu Ma15Kai Yu Ma16Martin B. D. Müller17Martin B. D. Müller18Tessa Sinnige19Janet R. Kumita20Samuel I. A. Cohen21Renée Seinstra22Gabriele S. Kaminski Schierle23Clemens F. Kaminski24Denise Barbut25Alfonso De Simone26Tuomas P. J. Knowles27Michael Zasloff28Ellen A. A. Nollen29Michele Vendruscolo30Christopher M. Dobson31Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry and Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, United KingdomMRC Laboratory for Molecular Cell Biology (LMCB) University College London, London, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United KingdomDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United KingdomMedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, United StatesDepartment of Life Sciences, Imperial College London, London, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomMedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, United StatesUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, NetherlandsDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomThe aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research.https://www.frontiersin.org/articles/10.3389/fcell.2021.552549/fullC. elegansParkinson's diseasealpha-synucleindrug discoveryprotein aggregationprotein misfolding |