alpha-synuclein and pyridine

Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation.

Topics: alpha-Synuclein; Amyloid; Humans; Lewy Bodies; Neuroprotective Agents; Parkinson Disease; Polymerization; Protein Aggregation, Pathological; Pyridines; Synucleinopathies

Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias.

Topics: alpha-Synuclein; Animals; Benzothiazoles; Corpus Striatum; Dopamine; Excitatory Amino Acid Antagonists; Impulsive Behavior; Male; Nucleus Accumbens; Parkinson Disease; Pramipexole; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Glutamate; Up-Regulation

The aggregation of alpha-synuclein (alphaS) has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and Parkinson's disease (PD). We used fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy to examine the effects of nicotine, pyridine, and N-methylpyrrolidine on the formation of alphaS fibrils (f alphaS) from wild-type alphaS (alphaS (WT)) and A53T mutant alphaS (A53T) and on preformed f alpha Ss. Nicotine dose-dependently inhibited the f alphaS formation from both alphaS (WT) and A53T. Moreover, nicotine dose-dependently destabilized preformed f alpha Ss. These effects of nicotine were similar to those of N-methylpyrrolidine. The anti-fibrillogenic activity of nicotine may be exerted not only by the inhibition of f alphaS formation but also by the destabilization of preformed f alphaS. Additionally, this effect may be attributed to N-methylpyrrolidine moieties of nicotine.

Topics: alpha-Synuclein; Benzothiazoles; Humans; Kinetics; Lewy Body Disease; Microfibrils; Microscopy, Atomic Force; Microscopy, Electron; Mutation; Nicotine; Nicotinic Agonists; Pyridines; Pyrrolidines; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Fluorescence; Thiazoles