In a groundbreaking study funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), researchers have made a significant discovery about a protein called phosphorylated α-synuclein, shedding new light on its involvement in various neurodegenerative diseases, including Parkinson's disease and Lewy body dementia. Published in the journal Neuron, the research challenges prevailing theories about the protein's role in these disorders and suggests a potential avenue for future treatments.

Phosphorylated α-synuclein is known to accumulate in protein clusters called Lewy bodies, thought to be toxic to neurons. Previous studies have primarily focused on understanding its association with diseases like Parkinson's and Lewy body dementias. However, this latest research reveals that phosphorylated α-synuclein is also involved in the normal functioning of neuronal communication in a healthy brain.

The researchers, led by Dr. Subhojit Roy from the University of California, San Diego, initially hypothesized that α-synuclein protein helped regulate excessive neuronal firing to maintain proper communication between neurons. To their surprise, they found that phosphorylation, a process where a phosphate ion is added to a specific amino acid, played a crucial role in the normal function of α-synuclein.

Through molecular modeling, the researchers discovered that phosphorylated α-synuclein undergoes a structural change that promotes interactions with other proteins in healthy brains. They also observed a relationship between increasing neural activity and an increase in the amount of phosphorylated α-synuclein. This suggests a potential link between synaptic activity and α-synuclein phosphorylation.

Moreover, the study found that phosphorylation is necessary for α-synuclein to assemble a network of proteins that bind synaptic vesicles, which are responsible for the release of chemicals that enable neurons to communicate. This discovery suggests that phosphorylated α-synuclein acts as a regulating mechanism, controlling the activity of specific neuronal circuits, akin to a brake or clutch system.

"This research challenges our previous understanding of phosphorylated α-synuclein solely as a marker for pathology in neurodegenerative diseases," said Dr. Beth-Anne Sieber, program director at NINDS. "These findings provide valuable insights into the origins of these disorders and may pave the way for more effective treatment approaches."

The constant presence of α-synuclein phosphorylation in certain brain regions suggests its importance in those areas. However, further studies are needed to unravel how low-frequency events in a healthy brain can lead to the pathological accumulation of phosphorylated α-synuclein and the formation of Lewy bodies, culminating in Parkinson's disease and Lewy body dementias.

While therapies targeting the phosphorylation of α-synuclein have been considered, it is essential to consider potential unintended consequences of blocking this process. Phosphorylated α-synuclein's role in maintaining functional neuronal circuits during peak activity periods highlights its potential value in preserving brain health.

This research, made possible by NINDS funding and supported by other organizations, contributes to our understanding of the intricate workings of the brain and lays the foundation for future advancements in diagnosing, preventing, and treating neurological diseases.

The National Institute of Neurological Disorders and Stroke (NINDS) remains at the forefront of funding research on the brain and nervous system. Its mission is to expand knowledge of these areas and utilize that knowledge to alleviate the burden of neurological diseases.

About the National Institutes of Health (NIH): NIH, the leading medical research agency in the United States, consists of 27 Institutes and Centers and operates under the U.S. Department of Health and Human Services. Recognized for its extensive support of basic, clinical, and translational research, the NIH is dedicated to investigating the underlying causes, treatments, and cures for a wide range of common and rare diseases.

With each breakthrough building upon past findings, basic research plays a pivotal role in advancing our understanding of human biology and behavior. It forms the bedrock for future developments that will transform the prevention, diagnosis, and treatment of diseases.

NIH remains committed to turning discovery into improved health outcomes as it continues to lead the charge in integrating scientific advancements into everyday medical practice.

Reference:
Parra-Rivas LA et al. Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function. Neuron. December 20, 2023. DOI: 10.1016/j.neuron.2023.11.020