With no cure to speak of, scientists are exploring every avenue possible when it comes improving therapies for Parkinson's disease, a condition affecting more than 10 million people around the world. A new study has opened up a promising pathway in this area, pinpointing a protein that plays a regulatory role in the neurodegeneration associated with the condition, and showing how it can be inhibited to protect key cells from damage.
Parkinson's disease is characterized by the death of cells in the brain that produce dopamine, which brings with it compromised motor function and symptoms such as tremors. As such, a lot of research in this area focuses on ways we might be able to preserve these vital populations of neurons, and this new study from scientists at the Medical University of South Carolina begins by focusing on genes that can prevent their destruction.
More specifically, the study focuses on a pair of proteins that can control the activity of these genes. Nrf2 is a protein that activates the expression of more than 250 genes that play a role in protecting neurons from inflammation and toxic oxidative stress, while Bach1 is a protein that prevents those genes from being activated. Analyzing the brains of autopsied Parkinson's disease patients, the scientists found that levels of Bach1 were heightened, with the same effect observed in pre-clinical models of the disease.
“This is the first evidence that Bach1 is dysregulated in Parkinson’s disease,” says study author Bobby Thomas.
The scientists then conducted experiments in mouse models of Parkinson's disease, in which Bach1 was removed from the equation. This protected some of the dopamine-producing neurons from stress-related destruction. They then analyzed the entire genomes of the mouse brains to determine which genes were activated.
“What we found was that Bach1 not only represses the expression of protective genes that are under the control of Nrf2, but it also regulates the expression of many other genes not directly regulated by Nrf2,” says Thomas. “So there are additional advantages to inhibiting Bach1 besides just activating Nrf2. Ideally you would want a drug that inhibits Bach1 and also activates Nrf2.”
In pursuit of such a drug, the scientists teamed up with a pharmaceutical company called vTv Therapeutics to develop a candidate called HPPE which functions as both a potent inhibitor of Bach1 and activator of Nrf2 in in vitro models. Testing the drug in mouse models then showed it could alleviate symptoms when administered before the disease or even after its onset, by switching on antioxidant genes and switching off ones that promote inflammation.
According to the scientists, the new drug outperformed existing, already-approved Nrft2 activators when it came to protecting neurons, and may induce fewer side effects. They hope to explore this in further studies, investigating what impacts long-term use of HPPE may have, and what potential it may carry in tackling other neurodegenerative conditions.
“This pathway may be beneficial whenever you have impairments in anti-inflammatory pathways or mitochondrial dysfunctions,” said Thomas. “I think any disease that has these kinds of etiologies would benefit from modulating this pathway.”
The research will be published this week in the journal Proceedings of the National Academy of Sciences.
