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dc.contributor.authorPerni, Michele
dc.contributor.authorvan der Goot, Annemieke
dc.contributor.authorLimbocker, Ryan
dc.contributor.authorvan Ham, Tjakko J.
dc.contributor.authorAprile, Francesco A.
dc.contributor.authorXu, Catherine K.
dc.contributor.authorFlagmeier, Patrick
dc.contributor.authorThijssen, Karen
dc.contributor.authorSormanni, Pietro
dc.contributor.authorFusco, Giuliana
dc.contributor.authorChen, Serene W.
dc.contributor.authorChalla, Pavan K.
dc.contributor.authorKirkegaard, Julius B.
dc.contributor.authorLaine, Romain F.
dc.contributor.authorMa, Kai Yu
dc.contributor.authorMüller, Martin B. D.
dc.contributor.authorSinnige, Tessa
dc.contributor.authorKumita, Janet R.
dc.contributor.authorCohen, Samuel I. A.
dc.contributor.authorSeinstra, Renée
dc.contributor.authorKaminski Schierle, Gabriele S.
dc.contributor.authorKaminski, Clemens F.
dc.contributor.authorBarbut, Denise
dc.contributor.authorDe Simone, Alfonso
dc.contributor.authorKnowles, Tuomas P. J.
dc.contributor.authorZasloff, Michael
dc.contributor.authorNollen, Ellen A. A.
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorDobson, Christopher M.
dc.date.accessioned2021-04-05T05:31:14Z
dc.date.available2021-04-05T05:31:14Z
dc.date.issued2021-03-22
dc.date.submitted2020-04-21
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/319470
dc.description.abstractThe 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.
dc.languageen
dc.publisherFrontiers Media S.A.
dc.subjectCell and Developmental Biology
dc.subjectC. elegans
dc.subjectParkinson's disease
dc.subjectalpha-synuclein
dc.subjectdrug discovery
dc.subjectprotein aggregation
dc.subjectprotein misfolding
dc.subjectneurodegenerative diseases
dc.subjecttransgenic model
dc.titleComparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease
dc.typeArticle
dc.date.updated2021-04-05T05:31:13Z
prism.publicationNameFrontiers in Cell and Developmental Biology
prism.volume9
dc.identifier.doi10.17863/CAM.66592
dcterms.dateAccepted2021-02-16
rioxxterms.versionofrecord10.3389/fcell.2021.552549
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.identifier.eissn2296-634X


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