α-Synuclein (αsyn) fibril formation is considered a central event in the pathogenesis of Parkinson’s disease (PD). In recent years, it has been proposed that prefibrillar annular oligomeric β-sheet-rich species, called protofibrils, rather than fibrils themselves, may be the neurotoxic species. The oxidation products of dopamine (DAQ) can inhibit αsyn fibril formation supporting the idea that DAQ might stabilize αsyn protofibrils. In the present work, through different biochemical and biophysical techniques, we isolated and structurally characterized αsyn/DAQ adducts. Contrary to protofibrils, we demonstrated that αsyn/DAQ adducts retain an unfolded conformation. We then investigated the nature of the modifications induced on αsyn by DAQ. Our results indicate that only a small fraction of αsyn interacts with DAQ in a covalent way, so that non-covalent interaction appears to be the major modification induced by DAQ on αsyn.

Dopamine quinones interact with a-synuclein to form unstructured adducts

BISAGLIA, MARCO;TOSATTO, LAURA;MUNARI, FRANCESCA;TESSARI, ISABELLA;POLVERINO DE LAURETO, PATRIZIA;MAMMI, STEFANO;BUBACCO, LUIGI
2010

Abstract

α-Synuclein (αsyn) fibril formation is considered a central event in the pathogenesis of Parkinson’s disease (PD). In recent years, it has been proposed that prefibrillar annular oligomeric β-sheet-rich species, called protofibrils, rather than fibrils themselves, may be the neurotoxic species. The oxidation products of dopamine (DAQ) can inhibit αsyn fibril formation supporting the idea that DAQ might stabilize αsyn protofibrils. In the present work, through different biochemical and biophysical techniques, we isolated and structurally characterized αsyn/DAQ adducts. Contrary to protofibrils, we demonstrated that αsyn/DAQ adducts retain an unfolded conformation. We then investigated the nature of the modifications induced on αsyn by DAQ. Our results indicate that only a small fraction of αsyn interacts with DAQ in a covalent way, so that non-covalent interaction appears to be the major modification induced by DAQ on αsyn.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2448316
Citazioni
  • ???jsp.display-item.citation.pmc??? 27
  • Scopus 77
  • ???jsp.display-item.citation.isi??? 75
social impact