A new therapeutic target identified against Parkinson’s disease

Researchers from the University of Barcelona (UAB) have discovered where, how and when a fundamental molecular mechanism for the development of Parkinson’s disease is triggered, which could allow the design of strategies to inactivate it, to prevent the onset of this disease.

The UAB team has identified a region in the early aggregates of the protein alpha-synuclein that can be targeted to prevent it from turning into the toxic amyloid fibrils that accumulate in the brains of people with Parkinson’s disease.

The discovery was recently published in Journal of the American Chemical Society – JACSin a study that advances the understanding of the structural properties of these initial aggregates, or oligomers, and paves the way for the development of new therapeutic strategies to inactivate them.

Aggregation of alpha-synuclein 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 into toxic amyloid fibrils that accumulate in the patient’s brain.

Alpha-synuclein oligomers play a key role in the development and progression of Parkinson’s disease and are therefore promising therapeutic and diagnostic targets, especially in the early stages of this disease, but their transient and highly dynamic nature limits the study of their structure and prevents the development of therapies to block them.

The researchers had observed in a previous study that a small molecule, the bacterial peptide PSMα3, inhibited alpha-synuclein aggregation by binding to oligomers, blocking conversion to fibrils and inhibiting neurotoxicity.

In the new study, they identified where, how and when this binding occurs in oligomers, uncovering a key region for the structural conversion process associated with the pathogenesis of Parkinson’s disease.

“We have identified the sequence of the structure that is essential for the conversion of oligomers to fibrils, thus opening a new field of exploration in the design of molecules that target oligomers. By harnessing this region, we can develop new molecules that mimic the properties of PSMα3 with much greater affinity and efficacy,” explains Salvador Ventura, director of the Protein Folding and Disease Research Group at the Institute of Biotechnology and Biomedicine (IBB) of UBB and coordinator of the study, in a statement.

By combining structural, biophysical and biochemical analyses, the researchers observed that PSMα3 acts by binding to one end of alpha-synuclein (N-terminus), which regulates the conversion process of the oligomer into fibrils. Upon binding, the peptide covers two small adjacent regions of the protein, P1 and P2, which have been shown to be critical for this pathogenic transition.

“This region is an ideal therapeutic target because it is recognized by peptides only when it is part of oligomers; this allows us to target the aggregates without affecting the functional monomeric form of alpha-synuclein, which is necessary for proper brain function,” says Ventura.

A region also relevant to inherited Parkinson’s disease

The study is also relevant for deepening the molecular mechanisms underlying hereditary Parkinson’s disease.

This variant, which usually affects younger people, is frequently associated with mutations located in the P2 region of alpha-synuclein, such as the G51D mutation, which produces one of the most aggressive forms of Parkinson’s disease.

The researchers demonstrated that the G51D mutation in the identified key region causes fluctuations that delay the conversion of the oligomer to fibrils. This delay would be the cause of an accumulation of long-lived, toxic oligomers that are not efficiently processed by the molecular chaperones that attempt to keep them disaggregated.

Instead, they capture essential elements from this disaggregation machinery that are necessary for the proper functioning of neurons. Failure or impairment of the protein control machinery to function properly could explain why this inherited mutation, as well as others, causes the early onset of Parkinson’s disease at an age when protein homeostasis is supposed to be preserved.

“Our discovery could lead to the development of specific peptides that can target these mutant forms of alpha-synuclein and thus to a personalized therapeutic approach for those suffering from hereditary Parkinson’s disease. We are already working on the development of these molecules”, stressed the Spanish researchers.