The aggregation of α-synuclein, a protein involved in neurotransmitter release at presynaptic terminals, is associated with a range of highly debilitating neurodegenerative conditions, most notably Parkinson’s disease. Intraneuronal inclusion bodies, primarily composed of α-synuclein fibrils, are the major histopathological hallmarks of these disorders, although small oligomeric assemblies are believed to play a crucial role in neuronal impairment. We have probed the mechanism of neurotoxicity of α-synuclein oligomers isolated in vitro using antibodies targeting the N-terminal region of the protein, and found that the presence of the antibody resulted in a substantial reduction of the damage induced by the aggregates when incubated with primary cortical neurons and neuroblastoma cells. We observed a similar behaviour in vivo using a strain of C. elegans overexpressing α-synuclein, where the aggregation process itself is also partially inhibited as a result of incubation with the antibodies. The similar effects of the antibodies in reducing the toxicity of the aggregated species formed in vitro and in vivo provides evidence for a common origin of cellular impairment induced by α-synuclein aggregates.
Probing the origin of the toxicity of oligomeric aggregates of α-synuclein with antibodies / Cascella R, Perni M, Chen SW, Fusco G, Cecchi C, Vendruscolo M, Chiti F, Dobson CM, De Simone A.. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8937. - STAMPA. - 14:(2019), pp. 1352-1362. [10.1021/acschembio.9b00312]
Probing the origin of the toxicity of oligomeric aggregates of α-synuclein with antibodies
Cascella RInvestigation
;Cecchi CConceptualization
;Chiti F
Supervision
;
2019
Abstract
The aggregation of α-synuclein, a protein involved in neurotransmitter release at presynaptic terminals, is associated with a range of highly debilitating neurodegenerative conditions, most notably Parkinson’s disease. Intraneuronal inclusion bodies, primarily composed of α-synuclein fibrils, are the major histopathological hallmarks of these disorders, although small oligomeric assemblies are believed to play a crucial role in neuronal impairment. We have probed the mechanism of neurotoxicity of α-synuclein oligomers isolated in vitro using antibodies targeting the N-terminal region of the protein, and found that the presence of the antibody resulted in a substantial reduction of the damage induced by the aggregates when incubated with primary cortical neurons and neuroblastoma cells. We observed a similar behaviour in vivo using a strain of C. elegans overexpressing α-synuclein, where the aggregation process itself is also partially inhibited as a result of incubation with the antibodies. The similar effects of the antibodies in reducing the toxicity of the aggregated species formed in vitro and in vivo provides evidence for a common origin of cellular impairment induced by α-synuclein aggregates.File | Dimensione | Formato | |
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