Genetic manipulation of urate alters neurodegeneration in mouse model of Parkinson's disease

December 17, 2012

A study by Massachusetts General Hospital researchers adds further support to the possibility that increasing levels of the antioxidant urate may protect against Parkinson's disease. In their report published in PNAS Early Edition, the investigators report that mice with a genetic mutation increasing urate levels were protected against the kind of neurodegeneration that underlies Parkinson's disease, while the damage was worse in animals with abnormally low urate.

"These results strengthen the rationale for investigating whether elevating urate in people with Parkinson's can slow progression of the disease," says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Diseases (MGH-MIND) and lead author of the PNAS report. "Our study is the first demonstration in an animal model that genetic elevation of urate can protect dopamine neurons from degeneration and that lowering urate can conversely exacerbate neurodegeneration."

Characterized by tremors, rigidity, difficulty walking and other symptoms, Parkinson's disease is caused by destruction of brain cells that produce the neurotransmitter dopamine. Healthy people whose urate levels are at the high end of the normal range have been found to be at reduced risk of developing Parkinson's disease. Studies led by Michael Schwarzschild, MD, PhD, director of Molecular Neurobiology Laboratory at MGH-MIND, showed that, among Parkinson's patients, symptoms appear to progress more slowly in those with higher urate levels. These observations led Schwarzschild and his colleagues to develop the SURE-PD (Safety of URate Elevation in Parkinson's Disease) clinical trial, conducted at sites across the country through the support of the Michael J. Fox Foundation. Expected in early 2013, the results of SURE-PD will determine whether a medication that elevates urate levels should be tested further for its ability to slow the progression of disability in Parkinson's disease.

The current study by Schwarzschild's team was designed to improve understanding of how urate protects against neurodegeneration. As in most animals, mice normally have very low levels of the antioxidant because it is broken down by the enzyme urate oxidase or uricase. The higher urate levels seen in humans and great apes were caused by inactivation of the uricase gene during primate evolution. The MGH-MIND team used two strains of genetically altered mice. In one, the gene for uricase is knocked out as it is in humans, increasing urate levels in the blood and brain; in the other strain, the gene is overexpressed, reducing urate levels even lower than usual for mice. Animals from both strains were used in a standard Parkinson's modeling procedure in which a neurotoxin is injected into the dopamine-producing brain cells on one side of the brain.

As expected, the brains of animals with genetically elevated urate levels showed significantly less damage from the neurotoxin injection than did the brains of genetically normal mice. The damage was increased even more in the mice with genetically reduced urate levels, which also exhibited reduced dopamine production and worsened movement abnormalities. The researchers confirmed that genetically altering uricase expression did not affect levels of other molecules in the metabolic pathway that includes urate, supporting attribution of the protective role to urate alone.

"The biology of urate in the brain is largely unexplored," says Schwarzschild, an associate professor of Neurology at Harvard Medical School. "Understanding both urate's mechanisms of protection and the way its levels are regulated in the body will help us determine how to better harness its protective effects, if they are substantiated. We now are searching for the mediators of urate's neuroprotection and beginning to explore how it is generated and transported in different brain cells."
-end-
Additional co-authors are Thomas Burdett, Cody Desjardins, Robert Logan, Sara Cipriani, PhD, and Yuehang Xu all of MGH-MIND. The study was supported by grants from the RJG Foundation, the Michael J. Fox Foundation, the American Federation for Aging Research Beeson Collaborative Program, by National Institutes of Health grants R21NS058324 and K24NS060991, and Department of Defense grant W81XWH-11-1-0150.

Massachusetts General Hospital (www.massgeneral.org), founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Dopamine Articles from Brightsurf:

Dopamine surge reveals how even for mice, 'there's no place like home'
''There's no place like home,'' has its roots deep in the brain.

New dopamine sensors could help unlock the mysteries of brain chemistry
In 2018, Tian Lab at UC Davis Health developed dLight1, a single fluorescent protein-based biosensor.

Highly sensitive dopamine detector uses 2D materials
A supersensitive dopamine detector can help in the early diagnosis of several disorders that result in too much or too little dopamine, according to a group led by Penn State and including Rensselaer Polytechnic Institute and universities in China and Japan.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Viewing dopamine receptors in their native habitat
A new study led by UT Southwestern researchers reveals the structure of the active form of one type of dopamine receptor, known as D2, embedded in a phospholipid membrane.

Significant differences exist among neurons expressing dopamine receptors
An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum.

How dopamine drives brain activity
Using a specialized magnetic resonance imaging (MRI) sensor that can track dopamine levels, MIT neuroscientists have discovered how dopamine released deep within the brain influences distant brain regions.

Novelty speeds up learning thanks to dopamine activation
Brain scientists led by Sebastian Haesler (NERF, empowered by IMEC, KU Leuven and VIB) have identified a causal mechanism of how novel stimuli promote learning.

Evidence in mice that childhood asthma is influenced by the neurotransmitter dopamine
Neurons that produce the neurotransmitter dopamine communicate with T cells to enhance allergic inflammation in the lungs of young mice but not older mice, researchers report Nov.

Chronic adversity dampens dopamine production
People exposed to a lifetime of psychosocial adversity may have an impaired ability to produce the dopamine levels needed for coping with acutely stressful situations.

Read More: Dopamine News and Dopamine Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.