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.

Trehalose-Induced Structural Transition Accelerates Aggregation of α-Synuclein.

Fibrillation of α-synuclein proceeds through distinct stages, with oligomers combining to form the seed or the nucleus, followed by exponential and saturation phases. Osmolytes are considered to act as protein stabilizers by virtue of their ability to inhibit protein aggregation. Trehalose, a non-reducing disaccharide which is conventionally used as a stabilizer, was found to order α-synuclein, a natively disordered protein, into a non-native conformation such that the protein folding pathway is driven towards aggregation.

Understanding Caffeine's Role in Attenuating the Toxicity of α-Synuclein Aggregates: Implications for Risk of Parkinson's Disease.

Epidemiological studies report a beneficial relationship between drinking coffee and the risk of developing Parkinson's disease (PD). This is likely due to caffeine, a constituent of coffee, acting as an adenosine A2A receptor antagonist. This study was planned to investigate whether caffeine has any effect on the aggregation of α-synuclein, present in Lewy bodies, the pathological hallmark of PD, which may account for this positive association.

Effect of endogenous Hsp104 chaperone in yeast models of sporadic and familial Parkinson's disease.

Molecular chaperones constitute a major component of the cellular stress response machinery in neurodegenerative diseases, many of which are characterized by the misfolding and aggregation of endogenous cellular proteins into generic amyloid macrostructures. Heterologous expression of the yeast protein remodelling factor Hsp104 has been proposed as a possible therapeutic approach in such disease conditions. Hsp104 is unique in its ability to act as a protein 'disaggregase' by removing smaller units from amyloid fibrils and has no homologue in metazoa.

Deciphering the roles of trehalose and Hsp104 in the inhibition of aggregation of mutant huntingtin in a yeast model of Huntington's disease.

Despite the significant amount of experimental data available on trehalose, the molecular mechanism responsible for its intracellular stabilising properties has not emerged yet. The repair of cellular homeostasis in many protein-misfolding diseases by trehalose is credited to the disaccharide being an inducer of autophagy, a mechanism by which aggregates of misfolded proteins are cleared by the cell. In this work, we expressed the pathogenic N-terminal fragment of huntingtin in Δnth1 mutant (unable to degrade trehalose) of Saccharomyces cerevisiae BY4742 strain.

Modulation of α-synuclein aggregation by dopamine in the presence of MPTP and its metabolite.

The neurotransmitter dopamine has been shown to inhibit fibrillation of α-synuclein by promoting the formation of nonamyloidogenic oligomers. Fibrillation of α-synuclein is accelerated in the presence of pesticides and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The aim of this study was to determine whether dopamine continues to have an adverse effect on the fibrillation of α-synuclein in the presence of MPTP and its metabolite 1-methyl-4-phenylpyridinum ion (MPP(+) ).