Researchers have published a study (“The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition”) in Nature Communications today that presents compelling new evidence about what a key protein called alpha-synuclein actually does in neurons in the brain.
“This study could unlock more information about this debilitating neurodegenerative disorder that can leave people unable to walk and talk,” said Giuliana Fusco, research fellow at St. John’s College, University of Cambridge and lead author of the paper. “If we want to cure Parkinson’s, first we need to understand the function of alpha-synuclein, a protein present in everyone’s brains. This research is a vital step towards that goal.”
More than 10 million people worldwide live with Parkinson’s disease, including actor Michael J. Fox who was diagnosed aged 29, singer Neil Diamond, comedian Billy Connolly, and musician Ozzy Osbourne. Parkinson’s can affect women, but men are more likely to have the disease. It is not yet known why people get Parkinson’s, but researchers think it’s a combination of age and genetic and environmental factors that cause the dopamine-producing nerve cells to die, affecting the body’s ability to move.
The new study looked at what was going on inside healthy conditions to help pinpoint what is going wrong in the cells of people with Parkinson’s. All cells in the body have a plasma membrane that protects cells and usually transports nutrients in, and clears toxic substances out.
“α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson’s disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterization of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles,” the investigators wrote.
“Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterize in vitro a mechanism by which αS stabilizes, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region.
“Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviors in vitro.”
“One of the top questions in Parkinson’s research is: what is the function of alpha-synuclein, the protein that under pathological conditions forms clumps that affect motor and cognitive abilities? Usually you discover a protein for its function and then you explore what is going wrong when disease strikes, in the case of alpha-synuclein the protein was identified for its pathological association, but we didn’t know what it did in the neuron,” explained Fusco. “Our research suggests that the alpha-synuclein protein sticks like glue to the inner face of the plasma membrane of nerve cells but not to the outer—a crucial new piece of information.”
The scientists used synthetic models to mimic brain cell membranes during the study.
According to Alfonso De Simone, PhD, from Imperial College London, and one of the authors of the paper, “When this protein is functioning normally it plays an important part in the mechanisms by which neurons exchange signals in the brain. But it has a dark side because it malfunctions and begins to stick together in clumps which eventually spread and kill healthy brain cells. Our research showed that this protein clings onto the inner face of the plasma membrane of brain cells, so we are slowly building a picture of this very complex disorder by studying the key function of alpha-synuclein.”
There are treatments and drugs available to Parkinson’s patients and the disease isn’t fatal, but nothing is available to reverse the effects of the disease. Introducing lifestyle changes including getting more rest and exercise can also alleviate symptoms.
“We have thousands of proteins in our bodies and until the function of this mystery protein is confirmed with more research, drug therapies cannot begin to be developed to tackle the origins of Parkinson’s disease in case medication accidentally affect a crucial purpose of the alpha-synuclein protein,” added De Simone.