Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson's disease.
Several retrospective epidemiological reports have indicated an inverse correlation between smoking and development of Parkinson's disease (PD). This has mostly been attributed to the neuroprotective role of nicotine in stimulating nicotinic acetylcholine receptors and dopaminergic neurons which are damaged in PD. One of the characteristic features of PD is the intraneuronal deposition of globular inclusions of the intrinsically disordered protein α-synuclein as Lewy bodies. Using in vitro and the well-validated yeast cell models, we show that nicotine also exerts a beneficial effect on aggregation of α-synuclein. The alkaloid increases the lag time of the nucleation step and reduces the build-up of the more toxic oligomeric species in a concentration-dependent manner. This results in lower oxidative stress in the cell, reduced cytotoxicity and increased cell survival. Structural studies using CD spectroscopy and fluorescence quenching showed that α-synuclein forms a transient complex with nicotine, distorting its native structure and altering its aggregation landscape such that the formation of oligomers is inhibited. As soluble oligomers are believed to modulate the mechanism of PD pathogenesis mainly by formation of pores in neuronal membranes, resulting in leaching of vital components of the cytoplasm with deleterious effects for the cell, our results provide a mechanistic rationale for the observed beneficial role of nicotine on the progression of the disease.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Jay
J
Kardani
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Ratnika
R
Sethi
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India. Electronic address: ipsita@niper.ac.in.
Ipsita
I
Roy
D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009538:Nicotine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization / Q000187:drug effects* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
C497604:SNCA protein, human; D051844:alpha-Synuclein; D009538:Nicotine
Amyloid fibrils; Fibrillation; Lag time; Nicotine; Oligomerisation