Perni, Michele;
van der Goot, Annemieke;
Limbocker, Ryan;
van Ham, Tjakko J;
Aprile, Francesco A;
Xu, Catherine K;
Flagmeier, Patrick;
... Dobson, Christopher M; + view all
(2021)
Comparative Studies in the A30P and A53T α-Synuclein <i>C. elegans</i> Strains to Investigate the Molecular Origins of Parkinson's Disease.
Frontiers in Cell and Developmental Biology
, 9
, Article 552549. 10.3389/fcell.2021.552549.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Comparative Studies in the A30P and A53T α-Synuclein <i>C. elegans</i> Strains to Investigate the Molecular Origins of Parkinson's Disease |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fcell.2021.552549 |
| Publisher version: | http://dx.doi.org/10.3389/fcell.2021.552549 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, C, elegans, Parkinson&apos, s disease, alpha-synuclein, drug discovery, protein aggregation, protein misfolding, neurodegenerative diseases, transgenic model |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10192148 |
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