Two gene-regulating molecules have been found to have a protective effect in the set of neurons most affected by the disease, and when their activity wanes, disease sets in. This discovery suggests new avenues by which the disease might be prevented or treated.
METHOD: They used genetically engineering mice to capture the genetic messages being translated into proteins in a specific population of cells. They then mapped the interactions of regulator genes with their target genes in the mouse brain, and used this new tool to interpret the changes they documented between normal mice and those suffering from Parkinson’s-like degeneration.
This led them to 2 molecules: proteins SATB1 and ZDHHC2, which are more abundant in the dopaminergic neurons in the SNpc (Substantia Nigra pars compacta) versus the VTA (ventral tegmental area). When the researchers reduced the abundance of these molecules in the brains of normal mice, rapid degeneration like that seen in Parkinson’s disease followed.
“Conventional gene activity profiling approaches would not have been able to identify SATB1 and ZDHHC2 as key protective factors because the levels of these proteins do not change. But even though they continue to be expressed within the neurons, it appears that their regulatory activity drops off and they no longer stimulate their target genes,” Brichta says. “We later found similar changes in activity in the brains of Parkinson’s patients, particularly those in the early stages.”
Their findings also challenge the prevailing thought as to the molecular origins of Parkinson’s: that VTA neurons had some sort of factor protecting them against the kind of degeneration seen in the SNpc.
“In an unexpected contradiction to current models, the proteins we found protect the SNpc. Because dopamine and its metabolites can be toxic, we can speculate that, in the course of evolution, SATB1 and ZDHHC2 arose to protect this particular set of sensitive neurons fromcell death,” Greengard says. “The discovery of these two molecules’ role in Parkinson’s may assist in the development of treatments, because they are potential new targets for drugs.”
The researchers believe their new strategy may also be useful in studies of other neurodegenerative diseases, including Alzheimer’s, spinal muscular atrophy, Huntington’s disease and ALS. http://newswire.rockefeller.edu/2015/08/10/new-research-sheds-light-on-the-molecular-origins-of-parkinsons-disease/
Parkinson’s disease is caused by the loss of dopamine-producing neurons in a midbrain region called the substantia nigra pars compacta (SNpc). Above, the SNpc dopamine neurons of a mouse brain appear in yellow. Credit: Laboratory of Molecular and Cellular Neuroscience at The Rockefeller University/Nature Neuroscience
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