Fox Foundation Funds Study to Validate Potential Disease-Modifying Target in Parkinson's

Duquesne University Times

If asked to name a symptom commonly associated with Parkinson's disease, many will say tremors or slowness of movement. Lesser-known symptoms however, can include loss of the sense of smell, autonomic dysfunction and depression. At end stages of the disease, some Parkinson's sufferers experience cognitive decline, which may be caused by shrinkage of the hippocampus in the brain. Located under the cerebral cortex, the hippocampus is associated with short-term and long-term memory.

Thanks to a $75,000 grant from The Michael J. Fox Foundation for Parkinson's Research (MJFF), Dr. Rehana Leak is conducting a one-year study to examine a protein that could potentially result in halting or slowing the spread of pathology through the brain and thereby modify disease progression and delay symptoms such as cognitive decline.

"There is a revolution occurring in the field where we're beginning to understand that Parkinson's is a systemic disorder," said Leak, assistant professor at the Mylan School of Pharmacy. "Researchers are hypothesizing that the disease actually begins in the gut and the olfactory system, and travels up, through the vagus nerve and through the brain to finally hit those regions that cause dementia when they're damaged."

Parkinson's disease is associated with high levels of the protein alpha-synuclein. In the Parkinson's brain, synuclein misfolds and aggregates into clumps, which causes abnormal function and cell death.

"This can be propagated from cell to cell to cell, and that is perhaps how Parkinson's disease pathology spreads," said Leak, whose study is focusing on whether another protein-ceruloplasmin-could protect against alpha-synuclein toxicity. Such a therapy could stop or curb the pathology from spreading through the brain.

In Parkinson's disease patients, ceruloplasmin levels are low in the cerebrospinal fluid, and low levels are associated with earlier onset of the disease. In addition, previous research shows that one part of the brain where ceruloplasmin levels are higher-the neocortex-is less vulnerable to protein misfolding stress, making ceruloplasmin a potential therapeutic target.

Ceruloplasmin has not been extensively explored as far as its role in the brain, according to Leak. "It's present in the blood, where it's a ‘copper chaperone,' so it guides copper around," explained Leak. "Some studies suggest that ceruloplasmin can protect against toxicity in the brain. For example, it protects the brain from pesticide toxicity and stroke, and it can also help prevent the toxicity associated with very high iron levels."

Utilizing a new model of Parkinson's disease developed by a researcher at the University of Pennsylvania's Perelman School of Medicine, Leak and her research team are introducing synuclein fibrils into the hippocampus region of mice to initiate cell death. Ceruloplasmin will then be introduced, via gene therapy, to see whether it can protect against cell death in the area.

"In the study, we are going to do two things: one is to decrease ceruloplasmin levels to see if toxicity gets worse, and the other is to increase ceruloplasmin levels to see if toxicity is prevented," said Leak.

Dr. Kuldip Dave, senior associate director of research programs at MJFF, emphasized the importance of the potential of Leak's research. "Validation of this target in this synuclein model may open up avenues to use this protein for disease-modifying therapy in the future," said Dave.

Leak's research marks the first study at Duquesne to be supported by a MJFF grant.

Duquesne University Times

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