Seeking the Cause of Parkinson's Disease

“We know that this protein plays a highly important role in a number of degenerative diseases including Parkinson’s, but nobody knows exactly what it does.” Robert Edwards, MD

The protein alpha-synuclein plays a central role in Parkinson’s disease. However, evidence indicates that synuclein can both protect against neural degeneration and cause Parkinson’s. This project aimed to understand this apparent functional contradiction using the function of synuclein as an entry point.

Scientists have long puzzled over what causes Parkinson’s disease and the mysterious role that a protein called alpha-synuclein plays in its development. Dr. Robert Edwards used his Weill Innovation Award to search for answers by visualizing how the protein helps release neurotransmitters in brain nerve cells – and what happens when that process goes awry.

To observe this activity, Dr. Edwards used a technique he developed in 2017 that relies on light and electron microscopy. He originally applied this procedure to study synuclein in cells from the adrenal gland. Now he has extended the work to synuclein in neurons, the most relevant system to understand the origin of Parkinson’s. 

“The more we understand about the normal function of the protein, the more ways we will have to manipulate synuclein to prevent Parkinson’s disease,” he says. “We know that this protein plays a highly important role in a number of degenerative diseases, including Parkinson's, but nobody knows exactly what it does.”

In nerve cells, synuclein is found at synapses, the sites where bubble-like vesicles fuse with a neuron’s surface to release a neurotransmitter onto the next cell. Dr. Edwards has found that synuclein helps the vesicle flatten into the cell’s surface – a step that leads to the recycling of the vesicle so more vesicles can be made and continue the process. 

In the absence of synuclein, however, the vesicle just sits there, neither collapsing nor recycling. The transmitter is still released, but without recycling, the entire process is disrupted because every time the vesicle fuses and releases its contents, it's depleted. With only a few dozen vesicles present at a synapse, and vesicles released several times per second, they are gone in a few seconds. Since the cell can't make any more, eventually vesicles will be depleted, and the synapse will stop working.

Dr. Edwards is preparing to observe this process in synuclein-carrying genetic mutations linked to Parkinson’s and expects to have results within the next year. “If they all have the same effect on the function of this protein, then that’s presumably how they cause a disease,” he says.

He credits the Weill Innovation Award with allowing him to continue his research by bridging a crucial funding gap that led to grants from the National Institutes of Health and the Michael J. Fox Foundation. “Multiple grants have been made possible by the Weill Award,” Dr. Edwards notes, “enabling us to continue this critical research, and I am very grateful.”

UCSF Weill Awards

Joseph DeRisi, PhD; Sam Pleasure, MD, PhD; and Michael Wilson, MD