The first mouse model genetically programmed to simulate motor deficits and brain alterations found in Parkinson’s disease and related disorders has been developed by a team of scientists at the University of California, San Diego; the University of California, San Francisco, and the Gladstone Institute of Neurological Disease. The research was led by Eliezer Masliah, M.D., of the UCSD Departments of Neurosciences and Pathology.
The investigators report in the Feb. 18 issue of Science that mice bred to express a human protein called alpha-synuclein in the brain develop protein deposits in specific brain regions associated with Parkinson’s disease, and also have impaired motor function.
"Previous studies have shown increased levels of this protein in the brain cells of Parkinson’s patients, but whether they were a cause or result of the disease has not been clear," said Masliah. "With these results we have demonstrated that alpha-synuclein is in fact involved in the onset of diseases such as Parkinson’s. The development of symptoms in these genetically altered mice resembles disease progression in humans. This gives us a new model for studying Parkinson’s disease and related disorders such as Alzheimer’s disease."
The overexpression of alpha-synuclein in the brain cells of the mice is consistent with the accumulation of this protein in Parkinson’s patients. Alzheimer’s disease is also characterized by an abnormal accumulation of proteins in neurons, and Alzheimer’s and Parkinson’s disease frequently overlap.
"For many of the chemical and pathological changes one finds in brain diseases, it is hard to tell if they are a cause or consequence of the disease," said study co-author Lennart Mucke, M.D., Professor of Neurology and Neuroscience at UCSF and Director of the Gladstone Institute of Neurological Disease in San Francisco. "Our findings in experimental models demonstrate for the first time that accumulation of human alpha-synuclien in neurons actually causes a number of alterations found in these human disorders, namely, an abnormal build-up of proteins in brain cells, a loss of specific neuronal connections, and impairments of motor skills. These results suggest that blocking the accumulation of alpha-synuclein might help prevent or treat Parkinson’s and related conditions."
In this study, the human gene for alpha-synuclein was inserted into fertilized mouse egg cells. The eggs were then implanted into mice, which produced offspring expressing the gene in neurons. Among the offspring were animals with high levels of protein in the brain; these animals have been used to develop a colony of transgenic mice that consistently develop brain pathology and symptoms resembling those in patients with Parkinson’s disease.
Parkinson’s disease results from the degeneration of specific brain cells that regulate the activity of other brain cells by releasing a chemical called dopamine.
"Previous models for Parkinson’s disease in mice have been achieved through chemical or surgical techniques that interfere with the dopaminergic system, but it is unclear whether these interventions simulate what triggers the disease in people," said Masliah.
In this model, a protein that is known to accumulate in humans with Parkinson’s disease predisposes the mice to the age-related degeneration of dopaminergic connections between brain cells, and to the development of motor deficits, the investigators say. This model sheds light on the role of alpha-synuclein in neurodegenerative disorders and will be useful in the development and testing of new drugs for these conditions, they add.
The study’s co-authors also include Edward Rockenstein, Margaret Mallory, Makoto Hashimoto, Isaac Veinbergs, Yutaka Sagara, Abbyanne Sisk and Ayako Takeda of the UCSD Department of Neurosciences.
The research was supported by the National Institute on Aging, The J. David Gladstone Institutes and the Spencer Family Foundation.
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