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polymer physics amphiphilic systems rod-like colloids reaction rates
alpha-synuclein clathrin

Aggregation of α-synuclein

Parkinson's disease is one of the most common degenerative disorders of the central nervous system. It affects over 6 million people worldwide, with one in ten bein diagnosed before the age of 50. Parkinson's disease is cause by the death of neuronal cells implicitly leading to a reduction of the neurotransmitter dopamine. The death of the dopaminergic neurons in the substantia nigra is still unknown, yet there are a number of pathological features commonly associated with Parkinson's disease.

α-synuclein is a small 14 kDA acidic protein found mainly in the neuronal tissue and plays an important role in the pathogenesis of Parkinson's disease. α-synuclein is an intrinsically disordered protein, with little or no structure in its native state. Also known as the protein-chameleon α-synuclein is known to adapt its secondary structure depending on the surrounding environment. It is mainly disordered in a solvent, it can curl into α helices near membranes and stretch into β-sheets in fibrils or amyloids. This protein can accumulate and give rise to higher order insoluble aggregates which can lead to the triggering of Parkinson's disease.

We have developed a highly coarse grained model to study the aggregation of α-synuclein. We model a protein as a chain of twelve particles that can change their internal states, and therby shape and interaction parameters, in response to the environment. A protein in the disordered state is modelled as a random chain of soft spheres. By transformations of some of the particles into spherocylinders and by rearrangement into a planar configuration, the protein can adopt an ordered state capable of forming fibrils.

In a first representation we coarse grained a protein into a single polymorph patchy-particle, that can change conformation depending on the environment. Simulation results show the formation of oligomers and fibrils by a direct nucleation-and-growth mechanism, by two-step-nucleation through the conversion of an oligomer into a fiber or vice versa, and by fibril-enhanced conversion of oligomers into fibrils[1].


1 A coarse-grained protein model with internal degrees of freedom. Application to alpha-synuclein aggregation
I.M. Ilie, W.K. den Otter and W.J. Briels
J. Chem. Phys 144, 085103 (February 2016)