The anti-parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species

Carolina A. Braga, Cristian Follmer, Fernando L. Palhano, Elias Khattar, Mônica S. Freitas, Luciana Romão, Saviana Di Giovanni, Hilal A. Lashuel, Jerson L. Silva, Debora Foguel

Research output: Contribution to journalArticle

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Abstract

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 α-synuclein (α-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 α-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 α-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.

Original languageEnglish
Pages (from-to)254-273
Number of pages20
JournalJournal of Molecular Biology
Volume405
Issue number1
DOIs
Publication statusPublished - 7 Jan 2011
Externally publishedYes

Fingerprint

Synucleins
Selegiline
Pharmaceutical Preparations
Poisons
Parkinson Disease
Dopaminergic Neurons
Dopamine
Oxidoreductases
Lewy Bodies
Dihydroxyphenylalanine
Movement Disorders
Neuroprotective Agents
Substantia Nigra

Keywords

  • α-synuclein
  • aggregates toxicity
  • dopamine
  • Parkinson's disease
  • selegiline

ASJC Scopus subject areas

  • Molecular Biology

Cite this

The anti-parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species. / Braga, Carolina A.; Follmer, Cristian; Palhano, Fernando L.; Khattar, Elias; Freitas, Mônica S.; Romão, Luciana; Di Giovanni, Saviana; Lashuel, Hilal A.; Silva, Jerson L.; Foguel, Debora.

In: Journal of Molecular Biology, Vol. 405, No. 1, 07.01.2011, p. 254-273.

Research output: Contribution to journalArticle

Braga, CA, Follmer, C, Palhano, FL, Khattar, E, Freitas, MS, Romão, L, Di Giovanni, S, Lashuel, HA, Silva, JL & Foguel, D 2011, 'The anti-parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species', Journal of Molecular Biology, vol. 405, no. 1, pp. 254-273. https://doi.org/10.1016/j.jmb.2010.10.027
Braga, Carolina A. ; Follmer, Cristian ; Palhano, Fernando L. ; Khattar, Elias ; Freitas, Mônica S. ; Romão, Luciana ; Di Giovanni, Saviana ; Lashuel, Hilal A. ; Silva, Jerson L. ; Foguel, Debora. / The anti-parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species. In: Journal of Molecular Biology. 2011 ; Vol. 405, No. 1. pp. 254-273.
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