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Molecular Regulators of Dopamine Synthesis

The death of certain brain cells known as nigrostriatal neurons, which produce the neurochemical known as dopamine, ultimately causes movement dysfunction and reduced quality of life for individuals with Parkinson's disease. Our laboratory is working to identify the normal functions of molecules implicated in Parkinson's disease in hopes of identifying ways to keep these neurons healthy and thereby preserving normal body movements. One of the molecules we study is alpha-synuclein, a small protein that has a tendency to accumulate inside neurons in Parkinson's disease and several other brain disorders. With regard to Parkinson's disease, knowing the normal function of alpha-synuclein in dopamine neurons should be beneficial for developing treatments for slowing or preventing the cell loss that results in the disease. Others discovered that alpha-synuclein has similarity to a family of molecules known as the 14-3-3 proteins, well-known stimulators of dopamine synthesis that contribute to many other normal cell functions as well. Our laboratory has found that alpha-synuclein can inhibit dopamine synthesis in cell cultures and in purely in vitro assays by interacting with key molecules necessary for dopamine production. We have also found that alpha-synuclein and other dopamine biosynthetic molecules localize together on the cellular organelles. Others have shown that 14-3-3 also localizes to these same organelles. Collectively, the data suggest that alpha-synuclein and 14-3-3 work in opposition to each other to maintain normal dopamine levels in neurons and do so in part by their location in the cells. To further explore this, and to identify possible points of intervention for enhancing neuron function, our studies are designed to determine if dopamine synthetic molecules become localized by interactions with 14 3 3 or alpha-synuclein and if so, does that alter the activity of the interacting molecules to affect dopamine levels. These studies hold promise to identify novel therapeutic targets to speed the development of Parkinson's disease therapies.

Final Outcome

Dr. Perez’s research revealed novel evidence that dopamine is synthesized at the mitochondrion. This may help explain why nigral neurons have so much mitochondrial damage in Parkinson’s disease, since dopamine is toxic. Dr. Perez plans to look at the effect of free radical damage in mitochondria in nigral neurons for future studies. 

Results of this work were published in the Journal of Biological Chemistry.


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