Tuning of Alpha-Synuclein Aggregation by Small Molecules and Bacterial Proteins

Abstract

Parkinson's disease affects a growing number of the population and involves motor complications due to the death of dopamine neurons. Cytosolic inclusions containing amyloid fibrils of α-synuclein are a hallmark of the disease and it is believed that the aggregation process (going from monomers to amyloid fibers) of alpha-synculein somehow causes neurodegeneration. The synuclein-rich inclusions share structural characteristics with amyloid fibers found in many other neurodegenerative disorders. In addition, many organisms employ amyloid structures for mechanical or biological functions; for example, amyloid fibers are the major component of microbial biofilms. Mature amyloid fibers of alpha-synculein may not be the source of cytotoxicity; instead, transient oligomeric structures may be most dangerous to the neuronal cells. To investigate molecular pathways leading to alpha-synculein amyloid fibers, and thereby get hints for how to combat Parkinson's disease in vivo, we have taken a unique approach that involves purified proteins, biophysical experiments in vitro, and small-molecule tools. We have found that strategic ring-fused 2-pyridone compounds (mimics of small peptides), can tune alpha-synuclein aggregation such that either inhibitory or templating oligomers accumulate. Moreover, a fine balance between templation and inhibition processes is evident since one particular 2-pyridone inhibits bacterial amyloid formation but promotes alpha-synuclein amyloid fibers. In analogy with the small molecule tools, we found that bacterial proteins can cross-react with alpha-synculein and inhibit as well as promote amyloid fiber formation at sub-stoichiometric levels. Direct interactions of alpha-synculein with bacterial proteins and/or natural metabolites may play a role in controlling Parkinson's disease in humans.