A new insight into Parkinson's disease protein

July 28, 2017 by Wallace Ravven, University of California, San Francisco
A new insight into Parkinson’s disease protein
Spots on a living primary mouse chromaffin cell represent individual dense core vesicles docked at the plasma membrane prior to exocytosis. Synuclein both reduces the number of vesicles fusing and increases the rate of those that do fuse. Credit: Robert Edwards lab

Abnormal clumps of certain proteins in the brain are a prominent feature of Parkinson's and other neurodegenerative diseases, but the role those same proteins might play in the normal brain has been unknown.

Now, new research by UC San Francisco neuroscientist Robert Edwards, MD, has uncovered the role of one such , known as , which has long been implicated in Parkinson's . Understanding how alpha-synuclein normally acts, he said, can provide direct clues to how it might fail, and may point the way to preventing or managing diseases including Parkinson's.

This finding is the first identification of a normal role for a signature protein central to neurodegenerative disease.

"The aggregation of alpha-synuclein in neurons is a hallmark of Parkinson's," Edwards said. "But we wanted to search for earlier events that might trigger the degenerative process."

Alpha-Synuclein in Healthy Nerve Cells

In healthy nerve cells, alpha-synuclein can be detected at synapses, the sites where bubble-like vesicles fuse with a neuron's surface to the signaling molecule dopamine, which is known to be depleted in Parkinson's, said Edwards, who was elected to the National Academy of Sciences in May 2017. "A disturbance in this membrane-fusing process would disrupt the normal communication between neurons required for essentially all brain activity."

As reported in Nature Neuroscience, in a series of imaging experiments with neurons and other cells from mice, Edwards's research team explored exactly how alpha-synuclein takes part in this crucial interaction.

The protein actually plays two roles, they found. When present in abnormally high amounts, as it is in Parkinson's, it can inhibit the fusion of vesicles with membranes, which is necessary for neurotransmitter release. But in normal amounts, it has a surprisingly different effect: if neurotransmitters are already being released, alpha-synuclein helps speed the process.

The question remains how one protein can have both negative and positive roles in transmitter release, and how the former might contribute to Parkinson's disease.

A smart guess might be that Parkinson's arises from an abnormal form of alpha-synuclein inhibiting . But Edwards, the John and Helen Cahill Family Endowed Chair in Parkinson's Disease Research, found strong evidence for a less intuitive explanation.

Mutations, Unknown Mechanisms

Several mutations in the synuclein gene are known to cause rare forms of Parkinson's that run in families. Edwards showed that they do so not by boosting synuclein's inhibitory effect, but by disrupting its normal ability to aid neurotransmitter release once it has started. "So when the negative effect is intact, but the positive role is blocked, the net result disrupts neurotransmitter release," he surmises. "This could lead to the impairment in dopamine release, and ultimately to cell death."

The vast majority of people with Parkinson's don't inherit it through mutations, but acquire it by unknown mechanisms. Edwards's research has convinced him that the more common form of the disease arises from a defect in alpha-synuclein's natural ability to speed .

He hasn't pinpointed a potential cause for this defect in most people with the disease, but thinks one suspect is phosphorylation, a cellular process that regulates normal protein function.

"By understanding the normal function of alpha-synuclein, and in particular its regulation, we're starting to understand how anyone can acquire Parkinson's disease," Edwards said. "We hope this can help develop therapy that targets the underlying degenerative process."

Explore further: Drug discovery: Alzheimer's and Parkinson's spurred by same enzyme

More information: Todd Logan et al. α-Synuclein promotes dilation of the exocytotic fusion pore, Nature Neuroscience (2017). DOI: 10.1038/nn.4529

Related Stories

Drug discovery: Alzheimer's and Parkinson's spurred by same enzyme

July 3, 2017
Alzheimer's disease and Parkinson's disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

Parkinson's is partly an autoimmune disease, study finds

June 21, 2017
Researchers have found the first direct evidence that autoimmunity—in which the immune system attacks the body's own tissues—plays a role in Parkinson's disease, the neurodegenerative movement disorder. The findings raise ...

Parkinson's disease protein plays vital 'marshalling' role in healthy brains

September 19, 2016
Researchers have uncovered the normal function of a protein associated with Parkinson's disease, giving clues about what happens when it malfunctions.

Pre-clinical study suggests Parkinson's could start in gut endocrine cells

June 15, 2017
Recent research on Parkinson's disease has focused on the gut-brain connection, examining patients' gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating ...

New mechanism behind Parkinson's disease revealed

June 5, 2017
Parkinson's disease is a debilitating neurological illness that affects approximately 10 million people worldwide. It is marked by a progressive decline in physical function, the most iconic being uncontrollable tremors, ...

A 'frenemy' in Parkinson's disease takes to crowdsourcing

September 29, 2014
The protein alpha-synuclein is a well-known player in Parkinson's disease and other related neurological conditions, such as dementia with Lewy bodies. Its normal functions, however, have long remained unknown. An enticing ...

Recommended for you

Link between IBD and Parkinson's might allow doctors to slow down condition

May 21, 2018
Doctors may be able to modify or slow down the progress of the neurological condition Parkinson's disease in the future by spotting signs of it in patients with inflammatory bowel disease (IBD), suggest a study published ...

Untangling brain neuron dysfunction in Parkinson's disease and dementia with Lewy bodies

May 10, 2018
A decay of brain function is a hallmark of Parkinson's disease and dementia with Lewy bodies, or DLB. Specifically, cognitive dysfunction defines DLB, and nearly eight of every 10 Parkinson's patients develop dementia.

Diverse Parkinson's-related disorders may stem from different strains of same protein

May 9, 2018
Different Parkinson's-related brain disorders, called synucleionpathies, are characterized by misfolded proteins embedded in cells. Researchers in the Perelman School of Medicine at the University of Pennsylvania found that ...

New study sheds light on the complex dynamics of Parkinson's disease

May 3, 2018
Parkinson's disease affects around 10 million people worldwide, yet exactly how the disease and treatments for its symptoms work remains a bit mysterious. Now, Stanford researchers have tested a seminal theory of Parkinson's ...

Researchers find that lipid accumulation in the brain may be an early sign of Parkinson's disease

April 29, 2018
A collaborative team of researchers at McLean Hospital, a Harvard Medical School affiliate, and Oxford University has found that elevated levels of certain types of lipids (fat molecules) in the brain may be an early sign ...

Eating fish could prevent Parkinson's disease

April 23, 2018
A new study from Chalmers University of Technology, Sweden, shines more light on the link between consumption of fish and better long-term neurological health. Parvalbumin, a protein found in great quantities in several fish ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.