New research finds that a ‘master regulator’ of the epigenome called TET2, may help protect the brain from inflammation and neurodegenerations associated in Parkinson’s Disease (PD).
The TET2 enzyme oxidizes 5-methylcytosines (5-mCs) to hydroxymethyl-cytosines (5-hmCs), promoting DNA demethylation. In cancer, TET2 is often mutated, and loss of TET2 function is associated with changes in epigenetic DNA methylation patterns. Methylation patterns influence how genes function without altering the genes themselves. TET enzymes have previously been shown to impact neurodevelopment and synaptic transmission.
In this study, published in Nature Neuroscience, researchers compared the neuronal nuclei from the prefrontal cortex brain tissue of 57 people with PD and 48 healthy volunteers. They observed elevated hydroxymethylation levels in PD, a result of up-regulated TET2 activity in PD patients. The TET2 enzyme caused certain genes to reset, essentially rebooting the genes and leading to a vigorous immune response leading to inflammation-induced neurotoxicity.
In studies of mouse brain challenged with the lipopolysaccharide test—a widely used model of inducing PD-like inflammation—neurons were protected from inflammation and neurodegeneration seen in PD after inactivating the TET2 enzyme. The researchers also used an infectious model to reduce the number of dopamine neurons in mice, similar to that observed in PD. Shutting down TET2 activity in this model suppressed pro-inflammatory gene activity, brain immune cell activation and the eventual death of neurons triggered by inflammation.
“Decreased TET2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD,” the authors write.
Because PD patients have elevated TET2 expression and a hypervigilant immune activity, that neuroinflammation may further trigger more TET2 expression. “This suggests a potentially reinforced feed-forward loop contributing to the overall neuroinflammation and neurotoxicity observed in PD patients,” the authors write.
Parkinson’s Disease remains a lethal disease with no effective long-term treatments. This study suggests that reducing TET2 activity may provide a new target for quieting the inflammatory responses and neurodegeneration observed in the disease. It points to a new direction in PD treatment; one that researchers hope will lead to new drugs preserving healthy neurons.
The authors suggest that compounds capable of inhibiting TET2 activity, like dimethyloxalyglycine (DMOG), could be helpful for PD. Earlier studies show DMOG is neuroprotective after traumatic brain injury and hypoxia.
“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” says senior author Viviane Labrie, PhD of the Van Andel Institute in Grand Rapids, Michigan. “Regulation of the epigenome could dampen an overactive immune system and protect against neurodegeneration.”