α-Synuclein Adopts an α-Helical Conformation in the Presence of Polyunsaturated Fatty Acids To Hinder Micelle Formation

Abstract

Alpha-synuclein is a small cytosolic protein involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Recent studies suggested a lipid-related function for this brain-enriched protein. Since the brain carries a high level of docosahexaenoic acid (DHA) and since the extent of alpha-synuclein gene expression increases in response to DHA intake, we have investigated the interaction of alpha-synuclein with this essential omega-3 fatty acid. We show that alpha-synuclein allows DHA to be present in a soluble rather than micellar form. Upon interaction with DHA, the normally unstructured alpha-synuclein rapidly adopts an alpha-helical conformation. Prolonged exposure to DHA, however, gradually converts alpha-synuclein into amyloid-like fibrils. These results identify a potential biological function for alpha-synuclein and define an omega-3-linked pathway leading to alpha-synuclein aggregation.

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

“…We show that αS is likely to aggregate via such an intermediate in the presence of TFE, suggesting that membrane-induced αS aggregation may also involve the formation of a helical intermediate. Furthermore, TFE-induced fibrils are β-sheet rich and resemble previously reported aggregates formed by C terminally truncated αS (11), as well as structures induced by detergent and lipid interactions (12,13), which may be linked to PD initiation and progression (14)(15)(16)(17).…”

“…We demonstrate that the formation of the TFE-induced intermediate is not significantly affected by any of the three PD-linked αS mutations, but that all three mutations do influence the overall rate of TFE fibril formation, indicating that the mutations exert their effects subsequent to the formation of the intermediate state. TFE-induced fibrils are ultrastructurally similar to species detected for αS 1-120 and 1-130 truncation mutants (11), and may be related to aggregates produced by interactions between αS and lipids and detergents (12,13), potentially indicating that TFE fibrils may be relevant for understanding PD progression.…”

Metabolismo, oxidação e implicações biológicas do ácido docosahexaenoico em doenças neurodegenerativas

“…95 A maior parte dos casos ocorre esporadicamente com o avanço da idade, sendo um importante fator de risco. 95 É caracterizada pela perda progressiva de neurônios dopaminérgicos e a deposição de corpos de inclusão intracelular na forma de corpos de Lewy e neuritos de Lewy. [95][96][97] O principal componente proteico desses depósitos é a α-sinucleína.…”

“…95 É caracterizada pela perda progressiva de neurônios dopaminérgicos e a deposição de corpos de inclusão intracelular na forma de corpos de Lewy e neuritos de Lewy. [95][96][97] O principal componente proteico desses depósitos é a α-sinucleína. 97 A α-sinucleína é uma proteína desdobrada caracterizada por sete repetições (KTKEGV) na região N-terminal; por uma região central hidrofóbica formada por resíduos 61-65 ( componente não β-amiloide); e por trechos acídicos na parte C-terminal.…”

“…98 Alguns estudos reportam que α-sinucleína pode interagir com ácidos graxos poli-insaturados, cuja interação promoveria a oligomerização da proteína. 95,96,98,99 Os níveis de DHA mostraram-se elevados nas áreas do cérebro contendo α-sinucleína em pacientes com PD, o que atraiu o interesse no estudo da interação entre DHA e α-sinucleína. 98,100 De Francheschi e colaboradores 98 mostraram que α-sinucleína interage com o DHA adquirindo uma conformação α-helicoidal e o estado físico do lipídio torna-se alterado.…”