Discovery: Modified alpha-synuclein is essential for nerve cell function

A common marker of neurological diseases may play role in healthy brains

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Phosphorylated alpha-synuclein, a modified form of the protein that forms toxic clumps in the brains of people with Parkinson’s disease and related disorders, appears to play an important role in the normal function of nerve cells, a study shows.

When it’s modified, alpha-synuclein binds to other essential proteins in nerve cells, suggesting a model whereby the protein suppresses the release of neurotransmitters, the chemicals nerve cells use to communicate.

“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, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), said in a press release.

Details of the finding were published in Neuron in “Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.”

The aggregation of alpha-synuclein into clumps called Lewy bodies is a hallmark feature of Parkinson’s disease and related conditions called synucleinopathies, such as Lewy body dementia. In Parkinson’s, the presence of Lewy bodies is thought to cause the death of neurons (nerve cells) responsible for making dopamine, a neurotransmitter.

Lewy bodies primarily contain a modified form of alpha-synuclein that’s been phosphorylated, meaning a phosphate ion has been attached to it. As a result, animal and cell-based studies have routinely used this modification as a marker for disease, while others have investigated enzymes that phosphorylate alpha-synuclein as potential drug targets.

“In most studies to date, the mere presence of [alpha]-synuclein phosphorylation is assumed to be a marker for pathology for certain disorders, like Parkinson’s and Lewy body dementias,” Sieber said. “Recently, there has been considerable interest in developing drugs that prevent [alpha]-synuclein phosphorylation as a way of treating these disorders.”

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 A missing link

Experiments that have sought to establish a disease-related role for phosphorylated alpha-synuclein have failed to find a clear link between phosphorylation, aggregation, and nerve cell toxicity, however.

In previous work, study lead Subhojit Roy, MD, PhD, a professor at the University of California, San Diego, found unexpectedly that phosphorylation was necessary for the normal function of alpha-synuclein in synapses, the tiny gaps where neurotransmitters are released between two nerve cells that let them communicate via impulses.

Here, Roy and his colleagues investigated the role of phosphorylated alpha-synuclein in synapses using a variety of methods.

Examining mouse brains found that, while unmodified alpha-synuclein was widely distributed throughout the brain, phosphorylated alpha-synuclein was restricted to a subset of regions such as the olfactory bulb, which is responsible for smelling, and the cerebellum, which is primarily involved in muscle control, including balance and movement.

Using cultured mouse neurons, phosphorylated alpha-synuclein appeared to act like a switch that promoted the abundance of the protein in synapses. But blocking phosphorylation suppressed the protein’s function. Both unexpectedly imply a normal biological role for phosphorylated alpha-synuclein, the researchers said.

Consistently, triggering activity in cultured neurons, either chemically or via electrical stimulation, led to an increase in phosphorylated alpha-synuclein levels without a change in total unmodified alpha-synuclein. Similar findings were observed when neuronal activity was stimulated in living mice, which showed a marked increase in phosphorylated alpha-synuclein in brain samples.

A new look at phosphorylation

Alpha-synuclein, controlled by phosphorylation, may act to attenuate, or dampen, synaptic function, the researchers suggested.

“In hindsight, we hadn’t been looking at synuclein phosphorylation the right way,” Roy said. “Take for instance the circuits in the olfactory bulb, which according to our data has high levels of phosphorylated [alpha]-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.”

Further experiments indicated activity-dependent phosphorylation of alpha-synuclein triggered the binding to a host of essential synaptic proteins, including VAMP2 and synapsin. Also, phosphorylation stimulated the alpha-synuclein-dependent clustering of synaptic vesicles, tiny sacs that store neurotransmitters.

Lastly, the team generated models of alpha-synuclein to investigate the structural impact of phosphorylation. Simulations found that phosphorylation appeared to stabilize the structure of alpha-synuclein via interactions between the negatively charged phosphate and positively charged alpha-synuclein amino acids, the building blocks of proteins.

Researchers speculated the stability conferred by phosphorylation facilitated the interaction between alpha-synuclein and its bind partners VAMP2 and synapsin.

“Our experiments support a physiologic role for [phosphorylated alpha-synuclein] at synapses, advocating a model where activity-induced [phosphorylation] triggers the interaction of [alpha-synuclein] with a network of synaptic proteins that eventually leads to physiologic attenuation of neurotransmitter release,” the researchers wrote. “Our collective data — and the proposed new model for the role of [phosphorylation] in [alpha-synuclein] function — offer a fresh conceptual platform that can serve as the foundation for a deeper understanding of the pathophysiologic transition of [alpha-synuclein] in synucleinopathies [disorders characterised by alpha-synuclein aggregation].”

The study was funded by NINDS, the Farmer Family Foundation, Aligning Science Across Parkinson’s, and the Michael J. Fox Foundation for Parkinson’s Research.