Changes to Nerve Cell Membrane May Promote Alpha-synuclein’s Toxic Turn

Changes in the composition of fat molecules on the membranes of nerve cells appear to change how the alpha-synuclein protein interacts with these same cell membranes, possibly promoting the aggregation that characterizes Parkinson’s disease, new research reports.

The study, “The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition,” was published in the journal Nature Communications.

Alpha-synuclein is a protein particularly abundant in the brain. When it misfolds and accumulates, building to toxic levels that kill cells, it is known to underlie a group of neurodegenerative disorders known as synucleinopathies, which includes  Parkinson’s disease.

In fact, mutations in the gene coding for alpha-synuclein have been linked to early onset forms of Parkinson’s.

To best understand the role of a misfolded protein in disease, however, researchers first need to better understand the protein’s role in conditions of health — a point under debate.

“One of the top questions in Parkinson’s research is: what is the function of alpha-synuclein, the protein that under pathological [disease-related] conditions forms clumps that affect motor and cognitive abilities,” Giuliana Fusco, PhD, the University of Cambridge and the study’s lead investigator, said in a university press release.

“Usually you discover a protein for its function and then you explore what is going wrong when disease strikes,” Fusco said. “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.”

Previous research suggests that alpha-synuclein is involved in regulating the release of neurotransmitters, via interaction with synaptic vesicles. These vesicles participate in neuron-to-neuron communication by fusing with the plasma membrane of nerve cells (neurons) to release neurotransmitters. (The plasma membrane defines the outermost membrane of every cell; this protective membrane allows cells to interact with the external environment in a controlled way, for instance, allowing the entry of nutrients and the discarding of wastes.)

The research team studied alpha-synuclein’s 3D structure when the protein is binding both to the inside and outside of a neuron’s plasma membrane. They used in vitro (lab) models to mimic membranes of nerve cells in the brain.

Their results showed that alpha-synuclein, specifically its most abundant form (called acetylated alpha-synuclein), strongly binds the inner side of the plasma membrane.

“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 [surface] — a crucial new piece of information,” Fusco said.

Further experiments found alpha-synuclein helps to stabilize the docking of synaptic vesicles to the plasma membrane.

“When this protein is functioning normally it plays an important part in the mechanisms by which neurons exchange signals in the brain” to communicate, said Alfonso De Simone, PhD, a study co-author and Imperial College London professor.

Researchers then looked at what happened upon an increase of lipid (fat) molecules, called gangliosides (GM), in the plasma membrane. A rise in these fat molecules is associated with neurodegenerative diseases.

Here, results showed that an increase in GM considerably enhanced the ability of alpha-synuclein to bind to the outside of the plasma membrane.

Alpha-synuclein clumping in neurodegenerative diseases such as Parkinson’s may be linked with such changes in lipid composition as people age, the investigators suggested.

“Taken together, these results reveal how lipid composition modulates the interaction of [alpha-synuclein] with the [plasma membrane] and underlie its functional and pathological behaviours in vitro,” they wrote.

Their findings also support the importance of basic research in a better understating of key players in diseases like Parkinson’s, essential for more effective therapies.

“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,” De Simone said, because a medication may “accidentally affect a crucial purpose of the alpha-synuclein protein.”

Added Fusco: “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.”