Toxic Proteins Related to Parkinson’s Disease Blocked By Natural Human Molecules

Scientists at the UAB and the UniZar have detected a human peptide located in the brain that prevents the α-synuclein aggregates associated with Parkinson’s disease and helps prevent their neurotoxicity. The research released in Nature Communications suggests that this may be one of the organism’s natural systems to combat aggregation. The learning might help establish new therapeutic and diagnostic techniques for Parkinson’s disease and other synuclein pathologies.

The death of neurons focused on the synthesis of dopamine, one of the brain’s primary neurotransmitters, wears away the motor and cognitive abilities of those with Parkinson’s disease. The loss of these neurons is associated with alpha-synuclein aggregation. Current studies reveal that oligomers, the initial aggregates of this protein, are the most pathogenic types of α-synuclein and account for the spreading of the disease in the brain.

As a result, one of the more appealing strategies in combating this condition is to reduce the effects of these oligomers and, therefore, reduce pathological development. Nevertheless, the fact that these aggregates do not present a defined construct and are naturally transitory renders it incredibly challenging to detect molecules that bind with sufficient strength to explore any medical application.

A scientific partnership between scientists from the Institute for Biotechnology and Biomedicine (IBB) at the Universitat Autònoma de Barcelona (UAB) and from the Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) of the Universidad de Zaragoza (UniZar) now could detect a human endogenous peptide which strongly and particularly connects to the α-synuclein oligomers, therefore preventing their aggregation and preventing their neurotoxicity, two procedures closely related to the neurodegenerative decline of Parkinson’s disease. The recognition and research of the peptide, called LL-37, was just recently published in Nature Communications.

Researchers explain that LL-37 engages with the toxic alpha-synuclein oligomers in a particular way and with strength above that of any peptide previously described, comparable to the strength displayed by antibodies. It hinders aggregation at a significantly reduced concentration and shields neuronal cells from being harmed.

TLL-37 is located naturally in the human organism, both in the brain and intestine, organs in which α-synuclein aggregation occurs in Parkinson’s disease. This suggests that LL-37’s activity may react to a mechanism created by the body to naturally combat this disease, the researchers added.

Enticed by this idea, scientists now wish to research how its expression can be controlled and if this approach can come to be a risk-free treatment with the potential to influence the course of the disease. Salvador Ventura, a researcher at the IBB and coordinator of the study, stated that there is an opportunity that a treatment for Parkinson’s disease already lies inside us and that it only requires a correct activation.

The identification of LL-37 was carried out under the framework of research analyzing the design and features of pathogenic oligomers with the purpose of neutralizing them in a particular way. The analyses show that helical peptides with a hydrophobic side and another positively charged side are optimal for this kind of activity. The tests permitted scientists to detect three molecules with anti-aggregation activity. On top of the human molecules, a second peptide present in bacteria and a third artificially made molecule were detected.

Along with representing a practical therapeutic option for Parkinson’s disease and other synuclein pathologies, the molecules detected in the research are encouraging resources for its diagnosis, considering that they discriminate between functional and toxic α-synuclein varieties.

Nunilo Cremades, a researcher at BIFI-UniZar and study co-coordinator, said that until now, there were no molecules with the ability to precisely and efficiently detected toxic α-synuclein aggregates; the peptides the team presented on these issues are one-of-a-kind and, for that reason, have exceptional potential as diagnostic and prognostic resources.

In the research, over 25,000 human peptides were computationally evaluated, and single-molecule spectroscopy techniques, along with protein engineering, were used, along with cell cultures in vitro utilizing toxic oligomers.

Originally published by Scitechdaily.com

Reference: “α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity” by Jaime Santos, Pablo Gracia, Susanna Navarro, Samuel Peña-Díaz, Jordi Pujols, Nunilo Cremades, Irantzu Pallarès and Salvador Ventura, 18 June 2021, Nature Communications.