The Anti-Parkinsonian Drug Selegiline Delays the Nucleation Phase of α-Synuclein Aggregation Leading to the Formation of Nontoxic Species

被引：78

作者：

Braga, Carolina A. ^{[1
]}

Follmer, Cristian ^{[1
]}

Palhano, Fernando L. ^{[1
]}

Khattar, Elias ^{[1
]}

Freitas, Monica S. ^{[1
]}

Romao, Luciana ^{[2
]}

Di Giovanni, Saviana ^{[3
]}

Lashuel, Hilal A. ^{[3
]}

Silva, Jerson L. ^{[1
]}

Foguel, Debora ^{[1
]}

机构：

[1] Univ Fed Rio de Janeiro, Programa Biol Estrutural, Inst Bioquim Med, Ctr Ciencias Saude, BR-21941590 Rio De Janeiro, RJ, Brazil

[2] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Dept Anat, Macae, RJ, Brazil

[3] Ecole Polytech Fed Lausanne, Lab Mol Neurobiol & Neuroprote, Brain Mind Inst, CH-1015 Lausanne, Switzerland

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2011年 / 405卷 / 01期

关键词：

selegiline; dopamine; Parkinson's disease; alpha-synuclein; aggregates toxicity; CIRCULAR-DICHROISM SPECTROSCOPY; DISEASE-ASSOCIATED MUTANTS; AMYLOID FIBRIL FORMATION; IN-VITRO; SECONDARY STRUCTURE; NEURODEGENERATIVE DISEASES; ALZHEIMERS-DISEASE; DOPAMINE; MECHANISM; MUTATIONS;

D O I：

10.1016/j.jmb.2010.10.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Parkinson's disease (PD) is a movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of intraneuronal inclusions called Lewy bodies, which are composed mainly of alpha-synuclein (alpha-syn). Selegiline (Sel) is a noncompetitive monoamino oxidase B inhibitor that has neuroprotective effects and has been administered to PD patients as monotherapy or in combination with L-dopa. Besides its known effect of increasing the level of dopamine (DA) by monoamino oxidase B inhibition, Sel induces other effects that contribute to its action against PD. We evaluated the effects of Sel on the in vitro aggregation of A30P and wild-type alpha-syn. Sel delays fibril formation by extending the lag phase of aggregation. In the presence of Sel, electron microscopy reveals amorphous heterogeneous aggregates, including large annular species, which are innocuous to a primary culture enriched in dopaminergic neurons, while their age-matched counterparts are toxic. The inhibitory effect displayed by Sel is abolished when seeds (small fibril pieces) are added to the aggregation reaction, reinforcing the hypothesis that Sel interferes with early nuclei formation and, to a lesser extent, with fibril elongation. NMR experiments indicate that Sel does not interact with monomeric alpha-syn. Interestingly, when added in combination with DA (which favors the formation of toxic protofibrils), Sel overrides the inhibitory effect of DA and favors fibrillation. Additionally, Sel blocks the formation of smaller toxic aggregates by perturbing DA-dependent fibril disaggregation. These effects might be beneficial for PD patients, since the sequestration of protofibrils into fibrils or the inhibition of fibril dissociation could alleviate the toxic effects of protofibrils on dopaminergic neurons. In nondopaminergic neurons, Sel might slow the fibrillation, giving rise to the formation of large nontoxic aggregates. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：254 / 273

页数：20

共 74 条

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