Exploring the Dual Role of Phosphorylated α-Synuclein in Healthy Neural Function

It has been found by researchers that phosphorylated α-synuclein, a protein linked to a number of neurodegenerative illnesses, including Parkinson's disease and Lewy body dementia, is also engaged in the regular processes of neuronal communication in a healthy brain.

Exploring the Dual Role of Phosphorylated α-Synuclein in Healthy Neural Function

Image Credit: National Institute of Neurological Disorders and Stroke

The National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health, provided funding for the study, which was published in Neuron. The process of adding a phosphate ion to a particular amino acid or protein building block, in this case, the protein α-synuclein, is known as phosphorylation. This protein's structure may alter as a result of this addition, altering the protein's level of activity.

The majority of research on phosphorylated α-synuclein has focused on its involvement in certain neurological conditions like Parkinson's disease and Lewy body dementia, where the protein aggregates known as Lewy bodies accumulate. The phosphorylation of the protein α-synuclein is assumed to be the trigger for many disorders, and these clumps are thought to be toxic to neurons.

In most studies to date, the mere presence of α-synuclein phosphorylation is assumed to be a marker for pathology for certain disorders, like Parkinson’s and Lewy Body dementias. Recently, there has been considerable interest in developing drugs that prevent α-synuclein phosphorylation as a way of treating these disorders. These findings challenge the current hypotheses about how these disorders may originate in the brain and may give insight into how we might better treat them.”

Beth-Anne Sieber, Program Director, National Institute of Neurological Disorders and Stroke

Prior research conducted by the laboratory of the University of California, San Diego Professor Subhojit Roy, MD, PhD, who is also the study's Senior Author, revealed that the α-synuclein protein in a healthy brain reduces excessive neuronal firing to control neural communication. During their investigation into this notion, Roy's team discovered something unexpected: phosphorylation was required for α-synuclein to function normally.

Image Credit: Giovanni Cancemi/Shutterstock.com

Image Credit: Giovanni Cancemi/Shutterstock.com

Roy and his colleagues, under the direction of Postdoctoral Researcher Leonardo Parra-Rivas, PhD, examined the structure of α-synuclein using a molecular modeling technique. They found that when α-synuclein is phosphorylated, its structure changes in a way that promotes interactions with other proteins in healthy brains.

Additionally, they noticed a correlation between elevated electrical or chemical neural activity and a rise in phosphorylated α-synuclein levels in both cultivated cells and mice brain tissue. This study raises the possibility that α-synuclein phosphorylation and synaptic activity are related.

Furthermore, studies demonstrate that phosphorylation is required for α-synuclein to function in binding up synaptic vesicles, which are pockets that release chemicals that allow neurons to communicate with other neurons and cells, as well as in slowing down neuronal activity. Thus, phosphorylated α-synuclein functions similarly to a clutch or brake to regulate activity in specific neural circuits, indicating that it may have an unexplored role in healthy brains.

In hindsight, we hadn’t been looking at synuclein phosphorylation the right way. Take, for instance, the circuits in the olfactory bulb, which, according to our data, has high levels of phosphorylated α-synuclein. The nose never stops smelling, so it needs to be active all the time. One hypothesis is that synuclein phosphorylation may have evolved as a safety mechanism to protect neuronal circuits that need to be hyperactive.”

Subhojit Roy, Professor, University of California.

Certain brain regions may require this particular biochemical state, as evidenced by the persistent presence of α-synuclein phosphorylation in specific regions. Further research is required to comprehend how comparatively infrequent events in a healthy brain can cause the pathological build-up of α-synuclein into Lewy bodies over the course of a lifetime, resulting in Lewy body dementias and Parkinson's disease.

Moreover, treatments aiming to prevent α-synuclein from being phosphorylated itself could have to take into account the inadvertent negative effects of inhibiting a mechanism that could aid in maintaining neuronal functionality during periods of high activity.

Source:
Journal reference:

Parra‐Rivas, L. A., et al. (2023). Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function. Neuron. doi.org/10.1016/j.neuron.2023.11.020.

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