Bacterial Peptide Inhibits Aggregation of α-Synuclein

Researchers here report on continued investigation of a bacterial peptide capable of disrupting misfolded α-synuclein aggregation. This aggregation is the driving pathology of Parkinson's disease. In other cases, such as for transthyretin amyloid, it has been possible to design small molecule drugs that interfere in harmful protein aggregation. While the bacterial peptide is toxic to cells, it is hoped that better understanding its interaction with α-synuclein will lead to non-toxic small molecules that can achieve the same disruption of protein aggregation, and thus a viable treatment for Parkinson's disease and other synucleinopathies.

Alpha-synuclein aggregation is a hallmark of Parkinson's disease and other synucleinopathies. It is a dynamic process in which the protein self-assembles to form oligomers that eventually develop toxic amyloid fibrils, which accumulate in the patient's brain. Alpha-synuclein oligomers play a key role in the development and progression of the disease and, therefore, are promising therapeutic and diagnostic targets, particularly in the early stages of the disease, but their transient and highly dynamic nature limits the study of their structure and hinders the development of therapies aimed at blocking them.

Researchers had observed in a previous study that a small molecule, the bacterial peptide PSMα3, inhibited the aggregation of alpha-synuclein in binding to oligomers, blocking the conversion to fibrils and inhibiting neurotoxicity. In this study, they identified where, how and when this binding occurs in the oligomers, uncovering a key region for the structural conversion process associated with the pathogenesis of Parkinson's disease. Researchers observed that PSMα3 acts by binding to one end of the alpha-synuclein (N-terminus) that regulates the oligomer-to-fibril conversion process. Upon binding, the peptide covers two small adjacent regions of the protein which have been found to be critical for this pathogenic transition.

"We identified the structure's sequence that is essential for the conversion of oligomers to fibrils, thus opening a new field of exploration in the design of molecules aimed at targeting oligomers. By leveraging this region, we can develop new molecules that mimic the properties of PSMα3 with a much higher affinity and efficacy."


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