Columbia University Medical Center

Defect in Signaling Protein May Contribute to Parkinson’s

Cholinergic neurons (green) in a sea of gabaergic neurons (red) in brain of mutant mouse/photo: A.H. Kottmann

Columbia researchers led by Andreas H. Kottmann, PhD, assistant professor of pathology and cell biology, have discovered that sonic hedgehog (Shh), a protein crucial for early embryonic development, is necessary for the proper balance between dopamine neurons and other neurons in the adult brain. Dopamine neurons, which produce the neurotransmitter dopamine, degenerate in Parkinson’s disease. The finding could lead to new treatments for Parkinson’s and other neurological disorders.

Postdoctoral fellow and first author Luis E. Gonzalez-Reyes found that a strain of mice in which dopamine neurons cannot express Shh developed progressive movement problems and changes in brain structure in late adulthood that were similar to those of Parkinson’s.

The researchers found that Shh produced by dopamine neurons supports the survival of two other types of neurons, cholinergic and gabaergic, with which dopamine neurons communicate. In a feedback loop, those neurons, in turn, produce GNDF, a survival factor for dopamine neurons.

Further experiments showed that Shh produced by dopamine neurons also regulates the levels of the neurotransmitter acetylcholine (ACh), which is released by cholinergic neurons. Altered ACh levels are known to cause many of the movement problems of Parkinson’s disease.

“Sonic Hedgehog Maintains Cellular and Neurochemical Homeostasis in the Adult Nigrostriatal Circuit” was published in Neuron on July 26, 2012.

The research was supported NIH grants 1D43 TW06221-03 and NS056312, NYS Department of Health NYSTEM SDH CO24293, the ALS Association, the American Parkinson’s Disease Association, the Michael J. Fox Foundation, the Thomas Hartman Foundation for Parkinson’s Research, and the Parkinson’s Disease Foundation.