Scientists find how to reduce toxic Parkinson’s-associated protein

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Researchers from the Universitat Autònoma de Barcelona (UAB) have made a groundbreaking discovery in the fight against Parkinson’s disease.

Published in the Journal of the American Chemical Society, their study reveals a key region in the early aggregates of the alpha-synuclein protein that could be targeted to prevent the formation of toxic amyloid fibrils.

These fibrils are known to accumulate in the brains of Parkinson’s patients and contribute to the progression of the disease.

The research team, comprising Salvador Ventura, Jaime Santos, Jordi Pujols, and Irantzu Pallarès from the Institute of Biotechnology and Biomedicine (IBB) and the Department of Biochemistry and Molecular Biology, focused on understanding the structural properties of alpha-synuclein oligomers.

These oligomers are initial protein aggregates that play a crucial role in the development and progression of Parkinson’s disease.

Alpha-synuclein aggregation is a dynamic process where the protein self-assembles into oligomers. These oligomers eventually evolve into amyloid fibrils, which are harmful to brain cells.

Because of their transient and dynamic nature, alpha-synuclein oligomers have been challenging to study, and developing therapies to block them has been difficult.

In their research, the UAB team built upon previous findings that a bacterial peptide, PSMα3, could inhibit the aggregation of alpha-synuclein by binding to these oligomers.

This binding prevents the oligomers from converting into fibrils and thereby inhibits the associated neurotoxicity.

The current study delves deeper, identifying the specific region within the oligomers where PSMα3 binds. This discovery highlights a crucial sequence that is essential for the oligomers’ conversion into fibrils.

Salvador Ventura, the director of the Protein Folding and Conformational Diseases Research Group at the IBB and the study’s coordinator, explained that by identifying this sequence, new molecules can be designed.

These molecules would mimic the action of PSMα3 but with increased affinity and efficacy, targeting the oligomers more effectively.

Through structural, biophysical, and biochemical analyses, the researchers pinpointed that PSMα3 binds to the N-terminus of the alpha-synuclein. This region contains two small adjacent segments, P1 and P2, critical for the pathological transition from oligomers to fibrils.

Ventura emphasized the therapeutic potential of targeting this region, as it appears in the oligomers but not in the functional monomeric form of alpha-synuclein, which is necessary for normal brain function.

The implications of this research extend to familial Parkinson’s disease, which typically affects younger individuals and is often linked to mutations within the P2 region of alpha-synuclein.

One such mutation, G51D, known for its aggressive impact on disease progression, causes conformational changes that delay the conversion of oligomers to fibrils.

This delay leads to an accumulation of toxic oligomers that overwhelm the cellular machinery responsible for maintaining protein balance.

The discovery opens up possibilities for developing specific peptides that target these mutated forms of alpha-synuclein, offering a personalized therapy approach for familial Parkinson’s disease.

Ventura and his team are already working on developing these molecules, aiming to translate their laboratory findings into clinical applications that could significantly alter the treatment landscape for Parkinson’s disease.

This research not only provides insight into the molecular underpinnings of Parkinson’s but also illustrates a promising pathway for developing targeted therapies that could halt or slow the progression of the disease in its early stages.

If you care about Parkinson’s disease, please read studies about Vitamin E that may help prevent Parkinson’s disease, and Vitamin D could benefit people with Parkinson’s disease.

For more information about brain health, please see recent studies about new way to treat Parkinson’s disease, and results showing COVID-19 may be linked to Parkinson’s disease.

The research findings can be found in the Journal of the American Chemical Society.

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