Towards a cure for Parkinson's disease: inhibition of alpha-synuclein aggregation

2018 edition

Samuel Peña Díaz

Introduction and objectives:

Parkinson’s Disease (PD), the second most prevalent neurodegenerative disorder in the world, is characterised by the loss of dopaminergic neurons in substantia nigra pars compacta. This neuronal death is related with the presence of intracellular inclusions named Lewy’s bodies and Lewy’s neurites. The main component of these clusters is α-synuclein (α-syn), an intrinsically disordered protein that forms amyloids aggregates in these disorders. Together with the formation of amyloid fibrils, cell to cell transmission and the ability to seed the aggregation of new fibrils suggests that α-syn behaves as a prion-like protein, and, therefore, PD might be a prion-like pathology. Preventing α-syn aggregation would preclud both, the formation of toxic entities and their transmission.

Material and methods:

In this context, we have developed a robust protocol to screen large chemical libraries in search of potent inhibitors of the aggregation. The inhibitory potential of 14,400 compounds was analysed by means of Thioflavin-T and transmission electron microscopy assays as well as light scattering and nanosight measurements, and the protein misfolding cyclic amplification reaction. We identified more than 40 chemically unrelated inhibitors. From these molecules que select one compound (SynuClean-D) to further test its inhibitor potency in a cellular and in vivo context.

Results:

We used a human neuroglioma cell model that express α-syn and accumulates aggregates inside the cells. We observed that, the number of cells without inclusions was significantly increased and the number of aggregates in all cells was reduced in presence of the compound. This led us to test the inhibitor capacity in a more complex model, Caenorhabditis elegans. The worms express human α-syn either in the muscular tissue or in the dopaminergic neurons. We observed an important reduction of cellular aggregates, a significant improvement of the mobility of the worms and, more important, a high protection of dopaminergic neurons activity in the presence of the compound.

Conclusions:

Therefore, SynuClean-D is a promising candidate for further pre-clinical and clinical studies.