Early synaptic dysfunction found in Parkinson's Disease

May 24, 2018 by Will Doss, Northwestern University
LRRK2 patient-derived dopaminergic neurons display synaptic defects. Neurons derived from healthy human controls showed normal synaptic vesicle densities in the synaptic terminal (upper image), whereas LRRK2 patients displayed sparse and enlarged vesicles (asterisks, lower image) indicative of defective synaptic function. Credit: Northwestern University

Northwestern Medicine scientists identified a cellular mechanism that leads to neurodegeneration in patients with Parkinson's disease, according to a study published in Proceedings of the National Academy of Sciences.

Dimitri Krainc, MD, Ph.D., chair and Aaron Montgomery Ward Professor of Neurology, was the senior author of the study, which demonstrated a link between defective synaptic vesicle endocytosis and accumulation of toxic oxidized .

When it accumulates in the brain, oxidized dopamine has been shown to mediate the death of dopamine-containing neurons, causing the common motor symptoms observed in Parkinson's disease (PD) patients, according to previous research conducted by Krainc and published in Science. While people naturally lose as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate for the loss of brain function, leading to disease.

"In our prior work, we found that oxidized dopamine is toxic to neurons," said Krainc, who is also director of the Center for Neurogenetics. "In this paper, we further explain how such oxidized dopamine is formed in synaptic terminals of neurons from patients with Parkinson's disease."

The process begins when a protein called auxilin is dysregulated by another protein, a mutated form of LRRK2. Normally, auxilin regulates the process of synaptic vesicle endocytosis, a mechanism that neurons use to replenish the chemical signals needed to communicate with each other.

In the current study, scientists found that mutations in LRRK2 lead to dysfunctional auxilin and consequently impaired synaptic vesicle endocytosis. This manifests in inefficient packaging of dopamine into synaptic vesicles and an eventual buildup of dopamine in Parkinson's neurons.

This pool of "extra" dopamine can be rapidly oxidized and become toxic to dopamine , according to the study.

"These findings suggest that early therapeutic intervention in dysfunctional presynaptic terminals may prevent downstream toxic effects of oxidized dopamine and neurodegeneration in PD," Krainc said.

In addition, these studies of genetic forms of Parkinson's disease help identify converging pathways in the pathogenesis of sporadic and familial PD, highlighting the importance of investigating such cellular mechanisms to identify specific targets for therapy.

"This study is another example of how the emergence of genetic causes of Parkinson's has helped us understand how develops and where to focus to identify key pathways and targets for drug development," Krainc said.

Explore further: Treating with antioxidants early in Parkinson's disease process may halt degeneration and improve neuronal function

More information: Maria Nguyen et al. LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson's disease, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1717590115

Related Stories

Treating with antioxidants early in Parkinson's disease process may halt degeneration and improve neuronal function

September 7, 2017
Northwestern Medicine scientists have identified a toxic cascade that leads to neuronal degeneration in patients with Parkinson's disease (PD) and figured out how to interrupt it, reports a study to be published September ...

Scientific discovery may change treatment of Parkinson's disease

March 22, 2017
When monitoring Parkinson's disease, SPECT imaging of the brain is used for acquiring information on the dopamine activity. A new study conducted in Turku, Finland, shows that the dopamine activity observed in SPECT imaging ...

Conversion of brain cells offers hope for Parkinson's patients

April 11, 2017
Researchers at Karolinska Institutet have made significant progress in the search for new treatments for Parkinson's disease. By manipulating the gene expression of non-neuronal cells in the brain, they were able to produce ...

New method maps the dopamine system in Parkinson's patients

February 14, 2018
With the aid of a PET camera, researchers from Karolinska Institutet in Sweden have developed a new method for investigating the dopamine system in the brains of patients suffering from Parkinson's disease. The method measures ...

New target for Parkinson's disease identified

February 28, 2017
Emory investigators have discovered a novel link between a protein called SV2C and Parkinson's disease (PD). Prior work had suggested that the SV2C gene was associated with the curious ability of cigarette smoking to reduce ...

Intracellular dopamine receptor function may offer hope to schizophrenia patients

December 9, 2016
Dopamine is a chemical in the brain that plays an important role in controlling movement, emotion and cognition. Dopamine dysfunction is believed to be one of the causes of disorders like Schizophrenia, Tourette's syndrome, ...

Recommended for you

New evidence sheds light on how Parkinson's disease may happen

June 14, 2018
Researchers at Baylor College of Medicine and Texas Children's Hospital have identified unexpected new key players in the development of an early onset form of Parkinson's disease called Parkinsonism. These key players are ...

Scientists unravel molecular mechanisms of Parkinson's disease

June 12, 2018
Detailed brain cell analysis has helped researchers uncover new mechanisms thought to underlie Parkinson's disease.

First photoactive drug to fight Parkinson's disease

June 8, 2018
An international team has designed the first potentially therapeutic photoactive drug, MRS7145, to fight Parkinson's disease, according to the new article in Journal of Controlled Release.

Researchers address sleep problems in Parkinson's disease

June 7, 2018
A team of researchers at VIB and KU Leuven has uncovered why people with a hereditary form of Parkinson's disease suffer from sleep disturbances. The molecular mechanisms uncovered in fruit flies and human stem cells also ...

Drugs that suppress immune system may protect against Parkinson's

May 31, 2018
People who take drugs that suppress the immune system are less likely to develop Parkinson's disease, according to a study from Washington University School of Medicine in St. Louis.

Early synaptic dysfunction found in Parkinson's Disease

May 24, 2018
Northwestern Medicine scientists identified a cellular mechanism that leads to neurodegeneration in patients with Parkinson's disease, according to a study published in Proceedings of the National Academy of Sciences.

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.