Florida/Swedish scientists develop new model for studying how Parkinson’s disease starts and progresses

Neuroscientists have demonstrated that a selected gene, when injected into rats, sets off the progressive brain cell destruction that causes human Parkinson’s disease—a discovery they believe provides a better model for investigating the disease process.

In related studies, one conducted solely at the University of Florida and the other involving a UF/Swedish collaboration, researchers found their gene transfer technique was a quick and easy way to replicate many of the hallmark features of Parkinson’s disease as it occurs in people. More than 1 million Americans, including actor Michael J. Fox and former U.S. Attorney General Janet Reno, are affected by the progressively disabling condition.

Although the discovery is not relevant to patient care, it provides scientists a new and highly effective approach to tracking how the brain neurons that produce dopamine—a chemical that controls limb movement—are damaged and subsequently die.

Both research teams demonstrated that the delivery of specific genes into the mid-brain region of rats triggered some of the cellular abnormalities and motor impairments that occur in people with the disease. In the two studies, genetically treated rats failed to exhibit robust Parkinsonian symptoms despite significant brain cell loss—an outcome that mimics the human condition in which symptoms rarely show up until half or more of the brain’s dopamine-producing cells are wiped out. The findings are reported in Human Gene Therapy (3/20) and the Journal of Neuroscience (4/1).

“We expressed a protein in the brain region most affected in Parkinson’s disease (the substantia nigra), which is mutated in a rare familial form of Parkinson’s,” said Ronald Klein, Ph.D., an assistant in the UF College of Medicine’s department of pharmacology and therapeutics, and lead author of the article in Human Gene Therapy.

“Now we can use this model to test new hypotheses—to express other factors associated with the disease to either block or exacerbate the cell loss.” Co-investigators included Edwin Meyer, Ph.D., in UF’s pharmacology and therapeutics department, and Michael King, neuroscientist with the Malcom Randall Veterans Affairs Medical Center, Gainesville.

In both studies, scientists injected the alpha-synuclein gene—mutations of which cause a rare form of Parkinson’s—into the substantia nigra where dopamine-producing cells degenerate. The delivery of this gene, in a harmless carrier molecule known as the adeno-associated viral vector, set in motion the progressive brain nerve cell damage that significantly reduces dopamine production. The researchers had previously discovered this viral vector has an affinity for infecting cells in the substantia nigra.

“Our success in generating Parkinsonian brain cell damage through targeted gene transfer is far simpler and faster than cloning transgenic mice for the same purpose, and the gene-delivery technique generates a more vigorous progression of Parkinson’s disease-like neuropathology,” said UF neuroscientist Ronald Mandel, who co-authored the Journal of Neuroscience article with Swedish researchers Deniz Kirik and Anders Bjorklund.

“We do not think our genetic approach will replace the use of transgenic mice in Parkinson’s research, but we have developed a different and very effective way to replicate certain features of the disease in animals,” said Mandel, who is affiliated with UF’s Evelyn F. and William L. McKnight Brain Institute. “Advantages of our model are that the gene-transporting virus that we used can be administered at any time in an animal’s life span to any specific site in the brain and potentially to different species. In addition, with our gene transfer method, we can induce the Parkinsonian cell damage in one hemisphere of an animal’s brain, so that we can observe what happens both in the gene-modified hemisphere and on the unaffected side of the brain.

“These are significant advantages since we can use each animal as its own control,” Mandel said. “This reduces the number of animals needed and allows us to more rapidly obtain answers to questions about Parkinson’s disease.”

Klein pointed out, “The type of gene transfer we performed offers specific advantages for modeling neurodegenerative diseases such as Parkinson’s, which are typically associated with certain parts of the brain and are age-related.”

Although scientists have previously expressed the alpha-synuclein gene in transgenic mice and mimicked several cardinal features of the disease, Klein said, “None of these models led to the single-most important damaging process associated with the disease—a selective loss of dopamine-producing cells in the substantia nigra.”

The UF/Swedish successes in genetically inducing a human-like form of Parkinson’s disease occur only five years after scientists discovered the link between the alpha-synuclein gene and Parkinson’s.

The original mutation, found in Greek and Italian families, was reported in a landmark paper published in 1997 in the journal Science.

Klein also noted the model is one in which alpha synuclein can be studied in combination with other genes linked to Parkinson’s disease.

“It is hoped that these approaches will help to uncover why dopamine neurons are selectively vulnerable during the pathogenesis of Parkinson’s disease, as well as lead to novel therapies including gene therapy for the disease,” he said.