Switching Off Influential Enzyme May Shield Brain From Parkinson-Related Damage

Switching off a “master regulator” of the epigenome called TET2 may protect the brain from the inflammatory damage and neurodegeneration caused by Parkinson disease (PD), according to study findings published this week in Nature Neuroscience.

In the first of its kind study, researchers sought to assess whether PD pathogenesis may involve the epigenetic control of enhancers that alter neuronal functions. "One of the biggest challenges in treating PD, 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," senior study author Viviane Labrie, PhD, an associate professor at Van Andel Institute, said in a statement. "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."

Researchers examined the DNA methylation at enhancers, genome-wide, in neurons of both patients with PD and healthy controls. In their findings, those with PD were characterized by overactive TET2, an enzyme responsible for managing the types of chemical marks that annotate DNA and affect gene activity. These marks, specifically their type and the pattern in which they're applied, determine how and when the instructions in genes are used without changing the genes themselves.

These increased levels of TET2 could have vital implications for those with PD as the epigenetic dysfunction linked to altered TET2 is known to affect genes involved in the reactivation of the cell cycle. While normal for other cell types, restarting the cell cycle could be fatal to neurons and further expedite the progression of PD.

In a separate study, researchers then examined the results of reducing TET2 activity in vivo via mouse models. Their findings in the mouse brain found that this action protected neurons from inflammatory insults and neurodegeneration associated with PD. In an additional model of infection that results in a loss of dopamine neurons relevant to PD, switching off the “master regulator” of TET2 was found to suppress pro-inflammatory gene activity, brain immune cell activation, and the eventual death of neurons triggered by inflammation.

"PD is a complex disease with a range of triggers. 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" said Labrie. "More work is needed before a TET2-based intervention can be developed, but that it is a new and a promising avenue that we already are exploring."

Reference

Marshall LL, Killinger BA, Ensink E, et al. Epigenomic analysis of Parkinson disease neurons identifies Tet2 loss as neuroprotective. Nat Neurosci. Published online August 17, 2020. doi:10.1038/s41593-020-0690-y