P1 Artificial Chromosome Transgenic Mice as models for Progressive Parkinson Disease
Development of Progressive Pre-clinical Models of PD, 2006
Although most cases of Parkinson's disease occur without a family history, there are examples of highly hereditary forms of the disease. One rare form of hereditary PD is caused by alterations in a gene for a protein called alpha-synuclein. One such alteration, a change in amino acid alanine at position 53 in the protein, to threonine (A53T), causes a hereditary form of PD that affects people in their 40's and 50's.
Many diseases that affect the brain are difficult to study in human beings at the level of cells and molecules because of the difficulty in obtaining brain tissue for study, particularly early in the disease process. Our research is directed toward developing animal models for PD so we can study how this disease develops and investigate whether there are interventions that can reverse, slow down or halt the disease. We have created strains of mice that carry the entire human alpha-synuclein gene. (A human gene may be introduced into a mouse's DNA by injecting it into a fertilized egg and allowing the DNA to incorporate into the mouse's own DNA -- the resulting animal is known as a transgenic mouse). We have one line of mice in which we introduced the normal alpha-synuclein gene and two other lines of mice in which we introduced the gene with the disease-causing A53T change. We have also created a mouse line that is missing the mouse's own alpha-synuclein.
We propose to breed lines of mice expressing the normal or mutant forms of human alpha-synuclein, in the absence of the mouse's own alpha-synuclein gene, and follow them for two years to see if the mice with a double dose of mutant form of alpha-synuclein develop any of the abnormalities seen in PD. Our studies will include testing the mice for how well they walk and move, examining their brains for loss of relevant nerve cells and for the abnormal clumps of alpha-synuclein seen in human PD patients, and measure the levels of dopamine and other related chemicals in their brains. If these mice develop PD, they will provide us with a means of determining what abnormalities are occurring early in the disease, thereby providing a system in which to test methods for early diagnosis and therapeutic intervention.
The researchers successfully generated the proposed mice lines. While these mice did not show overt dopaminergic degeneration, an interesting gastrointestinal phenotype was observed. In the mice expressing human alpha-synuclein, the investigators observed deficits in gastrointestinal (GI) function. Dr. Nussbaum received a supplemental award from MJFF to further characterize these mice as possible tools for testing treatments to address the GI dysfunction (such as constipation, nausea and bloating) seen in patients with Parkinson's disease.
Chief, Division of Medical Genetics at University of California, San Francisco School of Medicine