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 behavior 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 provide 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, S. W.; Fusco, G.; Cecchi, C.; Vendruscolo, M.; Chiti, F.; Dobson, C. M.; De Simone, A.. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8929. - 14:6(2019), pp. 1352-1362. [10.1021/acschembio.9b00312]

Probing the Origin of the Toxicity of Oligomeric Aggregates of α-Synuclein with Antibodies

De Simone A.
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 behavior 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 provide evidence for a common origin of cellular impairment induced by α-synuclein aggregates.
2019
Probing the Origin of the Toxicity of Oligomeric Aggregates of α-Synuclein with Antibodies / Cascella, R.; Perni, M.; Chen, S. W.; Fusco, G.; Cecchi, C.; Vendruscolo, M.; Chiti, F.; Dobson, C. M.; De Simone, A.. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8929. - 14:6(2019), pp. 1352-1362. [10.1021/acschembio.9b00312]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/828847
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