Researchers at Van Andel Institute found switching off a molecular “master regulator” may protect the brain from damage in Parkinson’s disease.
The study, recently published in Nature Neuroscience, is the first of its kind and points to an entirely new avenue for developing therapies that preserve vulnerable brain cells in Parkinson’s disease. Currently, there are no effective ways to prevent Parkinson’s or to slow or stop its progression.
“One of the biggest challenges in treating Parkinson’s, other than the lack of therapies that impede disease progression, is that the disease has already laid waste to significant portions of the brain by the time it is diagnosed,” said Dr. Viviane Labrie, an associate professor at Van Andel Institute and the study’s senior author. “If we can find a way to protect critical brain cells from Parkinson’s-related damage early on, we could potentially delay or even prevent symptom onset.”
The study centered on a “master regulator” of the epigenome TET2, an enzyme responsible for managing the types of chemical marks that annotate DNA and affect gene activity. These marks determine how and when the instructions in genes are used without changing the genes themselves.
Labrie and her colleagues analyzed the brains of people with Parkinson’s alongside healthy controls. They found TET2 was overactive in Parkinson’s disease and that epigenetic dysfunction linked to altered TET2 affected genes involved in the reactivation of the cell cycle and heightened immune response. While restarting the cell cycle is normal for other cell types, it is fatal to neurons.
Additionally, their findings showed reducing TET2 activity in the brains of mice protects neurons from inflammatory damage and the subsequent neurodegeneration that is a hallmark of Parkinson’s. Using a model of infection that results in a loss of dopamine neurons relevant to Parkinson’s, the team also found TET2 inactivation suppressed pro-inflammatory gene activity, brain immune cell activation and the eventual death of neurons triggered by inflammation.
Taken together, the findings suggest calming TET2 activity may one day be a powerful preventative measure. In the future, such a strategy could be employed after a person experiences a major inflammatory event, such as an infection, to alleviate residual inflammation without interfering with its normal, healthy role in the body.
“Parkinson’s is a complex disease with a range of triggers,” Labrie said. “Temporarily reducing TET2 activity could be one way to interfere with multiple contributors to the disease, especially inflammatory events, and protect the brain from loss of dopamine-producing cells. More work is needed before a TET2-based intervention can be developed, but that it is a new and promising avenue that we already are exploring.”
Other VAI authors of the study include Lee Marshall, Ph.D.; Elizabeth Ensink; Peipei Li, Ph.D.; Katie Li; Wei Cui, Ph.D.; Noah Lubben; Xinhe Wang; Juozas Gordevicius, Ph.D.; and Gerhard A. Coetzee, Ph.D.
Matthew Weiland and Stefan Jovinge, M.D., Ph.D., of the DeVos Cardiovascular Research Program, a joint effort between VAI and Spectrum Health, also co-authored the study, along with Bryan Killinger, Ph.D., of Rush Medical College, and Jiyan Ma, Ph.D., formerly of VAI.
The VAI Flow Cytometry Core, Genomics Core, Bioinformatics and Biostatistics Core, Pathology and Biorepository Core, Vivarium and Transgenics Core, and the CAHM Sequencing Facility supported this work.
Brain tissue was provided by the Parkinson’s UK Brain Bank, the NIH NeuroBioBank and the Michigan Brain Bank.