Researchers at the Van Andel Institute have discovered that levels of Tet2, an epigenetic protein that regulates methylation levels, appeared to play a role in both inflammation and neuronal death in Parkinson's disease (PD).

The findings suggest potential strategies to treat or perhaps even prevent PD, which is the most common neurodegenerative disease after Alzheimer's disease (AD), affecting roughly 6 million individuals globally.

Tet2 mutations have also been implicated in cancer, which points to the need for caution in targeting the enhancer.

"If this were to be a therapeutic target, it's not that we want to turn off Tet2 for the rest of this person's life," Viviane Labrie told BioWorld Science. Instead, the goal would be to "tap the brake on inflammation to allow it to resolve."

Labrie is an associate professor at the Van Andel Institute and the senior author of the paper describing the work, which appeared in the August 17, 2020, online issue of Nature Neuroscience.

In a broader sense, Labrie's laboratory looks at the relationship between epigenetic and genetic factors in PD and AD.

Epigenetics are interesting to her, she said, because "Epigenetics can be modified by your DNA code, but [are] also a biological mechanism for how the environment can affect gene expression."

In PD, genetics seem to play a rather weak role in determining who will be afflicted.

Most cases are sporadic, and there are environmental risk factors that have been linked to the disease because they kill dopaminergic cells in the substantia nigra.

Those risks include both exposure to certain pesticides, and contaminants of synthetic heroin.

In their work, the team looked at the methylation patterns of enhancers, genetic elements that cooperate with promoters to increase gene expression.

Of more than 900,000 methylation sites in the prefrontal cortex they looked at, roughly 1,800 showed differences between PD patients and aged controls.

Those enhancers were involved in the regulation of nearly 3,000 genes. Among the target genes were several known risk genes for PD.

There was also Tet2.

"We really didn't expect to see Tet2, and when we found that, we were really excited," Labrie said.

The team then showed that when they manipulated Tet2 in an animal model of PD, "the neurons were completely protected from ... the effects of inflammation," she added.

Shutting down Tet2 both protected mice from dopaminergic cell death in the substantia nigra, which is the cause of motor dysfunction in PD, and prevented changes in gene expression that are normally induced by inflammation.

Labrie said that to date, the changes her team found in Tet2 appeared to be specific to brains with PD. Methylation abnormalities also occur in other neurodegenerative diseases, she said, but "the processes were different."

That said, her team plans to "explore the regulation of Tet2 in the context of other pathological processes, especially synucleopathies."

Mechanistically, "I don't at this point know what the connection between synuclein and Tet2 is," she said. Synuclein aggregates are clearly neurotoxic. But there are some patients in whom there is neuronal death in the absence of synucleinopathy, suggesting the aggregates may not be the ultimate cause of neuronal death, or they may not be the only cause of neuronal death (Marshall, L.L. et al. Nat Neurosci 2020, Advanced publication).