Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease

Michele Perni, Annemieke van der Goot, 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, Martin B.D. Müller, Tessa Sinnige, Janet R. Kumita, Samuel I.A. Cohen, Renée SeinstraGabriele 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number552549
JournalFrontiers in Cell and Developmental Biology
Publication statusPublished - 22 Mar 2021

Bibliographical note

Funding Information:
CK acknowledged funding from the UK Engineering and Physical Sciences Research Council, EPSRC (grants EP/L015889/1 and EP/H018301/1), the Wellcome Trust (grants 3-3249/Z/16/Z and 089703/Z/09/Z) and the UK Medical Research Council, MRC (grants MR/K015850/1 and MR/K02292X/1), MedImmune, and Infinitus (China) Ltd. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 722380, and from the Cambridge Centre for Misfolding Diseases. FA thanks UK Research and Innovation (Future Leaders Fellowship MR/S033947/1) and the Alzheimer’s Society, United Kingdom (317, 511) for support. EAAN acknowledged support from a European Research Council (ERC) starting grant (281622 PDControl) and a RIDE grant from NWO (948-00-017).

Publisher Copyright:
© Copyright © 2021 Perni, van der Goot, Limbocker, van Ham, Aprile, Xu, Flagmeier, Thijssen, Sormanni, Fusco, Chen, Challa, Kirkegaard, Laine, Ma, Müller, Sinnige, Kumita, Cohen, Seinstra, Kaminski Schierle, Kaminski, Barbut, De Simone, Knowles, Zasloff, Nollen, Vendruscolo and Dobson.


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