Scientists develop transgenic mouse that models parkinson's related disorders

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.