In vitro neurotoxicity of salsolinol is attenuated by the presynaptic protein α-synuclein.

Autor: do Carmo-Gonçalves P; Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Coelho-Cerqueira E; Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Cortines JR; Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., de Souza TLF; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Romão L; Campus Xerém, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Follmer C; Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil. Electronic address: follmer@iq.ufrj.br.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. General subjects [Biochim Biophys Acta Gen Subj] 2018 Dec; Vol. 1862 (12), pp. 2835-2845. Date of Electronic Publication: 2018 Sep 03.
DOI: 10.1016/j.bbagen.2018.08.022
Abstrakt: Background: Salsolinol (SALSO), a product from the reaction of dopamine (DA) with acetaldehyde, is found increased in dopaminergic neurons of Parkinson's disease (PD) patients. The administration of SALSO in rats causes myenteric neurodegeneration followed by the formation of deposits of the protein α-synuclein (aS), whose aggregation is intimately associated to PD.
Methods: NMR, isothermal titration calorimetry and MS were used to evaluate the interaction of SALSO with aS. The toxicity of SALSO and in vitro-produced aS-SALSO species was evaluated on mesencephalic primary neurons from mice.
Results: SALSO, under oxidative conditions, stabilizes the monomeric state besides a minor population of oligomers of aS, resulting in a strong inhibition of the fibrillation process. SALSO does not promote any chemical modification of the protein. Instead, the interaction of SALSO with aS seems to occur via hydrophobic effect, likely mediated by the NAC (non-amyloid component) domain of the protein. aS-SALSO species were found to be innocuous on primary neurons, while SALSO alone induces apoptosis via caspase-3 activation. Importantly, exogenous aS monomer was capable of protecting neurons against SALSO toxicity irrespective whether the protein was co-administered with SALSO or added until 2 h after SALSO, as evidenced by DAPI and cleaved-caspase 3 assays. Similar protective action of aS was found by pre-incubating neurons with aS before the administration of SALSO.
Conclusions: Interaction of SALSO with aS leads to the formation of fibril-incompetent and innocuous adducts. SALSO toxicity is attenuated by aS monomer.
Significance: aS could exhibit a protective role against the neurotoxic effects of SALSO in dopaminergic neuron.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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