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GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro

Fazzari, Maria; Di Biase, Erika; Zaccagnini, Ludovica; Henriques, Alexandre; Callizot, Noëlle; Ciampa, Maria Grazia; Mauri, Laura; ... Lunghi, Giulia; + view all (2023) GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids , 1868 (9) , Article 159350. 10.1016/j.bbalip.2023.159350.

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Abstract

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate.

Type: Article
Title: GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro
Location: Netherlands
DOI: 10.1016/j.bbalip.2023.159350
Publisher version: https://doi.org/10.1016/j.bbalip.2023.159350
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: GM1 ganglioside, GM1 oligosaccharide, Parkinson's disease, Plasma membrane signaling, α-Synuclein
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 > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10173139
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