Abstract
Aggregation of alpha-synuclein leads to the formation of Lewy bodies in the brains of patients affected by Parkinson's disease (PD). Native human alpha-synuclein is unfolded in solution but assumes a partial alpha-helical conformation upon transient binding to lipid membranes. Annealing Molecular Dynamics (AMD) was used to generate a diverse set of unfolded conformers of free monomeric wild-type alpha-synuclein and PD-associated mutants A30P and A53T. The AMD conformers were compared in terms of secondary structure, hydrogen bond network, solvent-accessible surface per residue, and molecular volume. The objective of these simulations was to identify structural properties near mutation sites and the non-amyloid component (NAC) region that differ between wild- type and disease-associated variants and may be associated to aggregation of alpha- synuclein. Based on experimental evidence, a hypothesis exists that aggregation involves the formation of intermolecular beta sheets. According to our results, disease-associated mutants of alpha-synuclein are no more propense to contain extended beta regions than wild-type alpha-synuclein. Moreover, extended beta structures (necessary for beta sheet formation) were not found at or around positions 30 and 53, or the NAC region in any unfolded conformer of wild-type, A30P or A53T alpha-synuclein, under the conditions of the simulations. These results do not support the hypothesis that the mutant's higher propensity to aggregation results solely from changes in amino acid sequence leading to changes in secondary structure folding propensity.
Highlights
Alpha-synuclein gene (SNCA) encodes a protein that is believed to integrate presynaptic signaling and membrane trafficking [1]
Parkinson’s disease is a degenerative neurological disorder characterized by rigidity, tremors, and bradykinesia
This is caused by loss of dopaminergic neurons
Summary
Alpha-synuclein gene (SNCA) encodes a protein (alpha-synuclein) that is believed to integrate presynaptic signaling and membrane trafficking [1]. Defects in the SNCA gene have been implicated in the pathogenesis of Parkinson’s Disease (PD) [2,3,4,5,6,7]. The accumulation of alpha-synuclein in the brain results in loss of dopaminergic neurons, with consequent reduction of striatal dopamine levels [9]. These protein aggregates are toxic enough to cause damage to the part of the brain responsible for motor movements, which is physically translated as slower movement and tremors. Mutations in SNCA are associated with rare familial cases of early-onset Parkinson’s disease. The mutations A30P and A53T have been linked to familial PD [12]
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