Brain protein pathway may be a key to Parkinson's disease

By Steve Tokar

Eric J. Huang, MD, PhD

A protein called HIPK2 is essential for the survival of dopamine neurons, the cells lost in Parkinson’s disease, according to a study in mice. The results suggest that the molecular pathway in which the protein functions could be a possible new target for therapy, the study authors say.

Parkinson’s disease is a degenerative disorder of the central nervous system in which dopamine neurons die. Normally, these cells produce the neurotransmitter dopamine, which transmits signals along brain pathways to allow smooth, coordinated function of the body’s muscles and movement. The loss of the cells leads to progressive impairment in motor skills and speech.

Scientists have speculated that HIPK2 might play a role in the survival of dopamine neurons, says principal investigator Eric J. Huang, MD, PhD, a staff physician at the San Francisco VA Medical Center, “but this is the first demonstration in a living organism that knocking out HIPK2 leads to the death of these cells.”

The study appears in the January 2007 issue of Nature Neuroscience. It was carried out using genetically engineered mice, developed in Huang’s lab, that lack the gene for HIPK2, which is a transcription factor—a protein that regulates the expression of genes.

In the study, the team demonstrated that lack of HIPK2 causes the absence of TGFbeta3, a neurotrophin—a protein that promotes the survival of brain and nerve cells. Lack of TGFbeta3 in turn leads to the death of dopamine neurons, resulting in mice that are born with Parkinson’s-like movement impairments.

Scientists do not know why dopamine neurons die in Parkinson’s disease, but the current finding suggests that TGFbeta3 deficiency may be a key, says Huang, who is also an associate professor of pathology at the University of California, San Francisco.

In the study, Huang and his research team compared the brains of the genetically engineered mice with those of normal, or wild-type, mice. They found that among the genetically engineered mice, the midbrains, where dopamine neurons are usually concentrated, had 40 to 50 percent fewer dopamine neurons.

“Our results support the model that HIPK2 and TGFbeta3 regulate the survival of dopamine neurons,” concludes Huang. “Whether we can actually manipulate this system to help Parkinson’s patients is unclear right now, and there are ongoing experiments to address that issue.”

Currently, the standard medication for Parkinson’s disease is the amino acid L-dopa, which is converted to dopamine in the brain. “It works to some extent, but a lot of patients suffer from side effects such as involuntary movement because of the uncontrolled release of the dopamine,” Huang notes. In addition, patients may develop a tolerance for the drug and require increasingly larger doses.

Huang and his research team are also using the mice as a model to test the hypothesis that one cause of Parkinson’s disease might be exposure to neurotoxins—substances in the environment that are poisonous to brain and nerve tissue. “We want to see if the HIPK2-TGFbeta3 pathway has a protective effect on dopamine neurons, and if the lack of that pathway makes those neurons more vulnerable to neurotoxin damage,” he says.

Lead authors of the study are Jiasheng Zhang, PhD, and Vanee Pho, PhD, of SFVAMC and UCSF; other collaborators include Stephen J. Bonasera, MD, PhD, Jed Holzmann, BS, Joanna Hellmuth, BS, Patricia H. Janak, PhD, and Laurence H. Tecott, PhD, of UCSF; and Amy T. Tang, BS, and Siuwah Tang, BS, of SFVAMC and UCSF.

The research was supported by funds from the Veterans Health Administration and by grants from the National Institute of Neurological Disorders and Stroke, the UCSF Alzheimer’s Disease Research Center, the National Parkinson’s Foundation, and the Michael J. Fox Foundation for Parkinson’s Research that were administered by the Northern California Institute for Research and Education.

NCIRE is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.