Switching Off TET2 Gene May Curb Inflammation, Loss of Neurons

Scientists have found that switching off TET2, a gene that provides instructions to make an enzyme that alters the activity of certain genes, can lower inflammation and neurodegeneration associated with Parkinson’s disease.

Authors of a study with those findings suggest that reducing the activity of this master gene regulator in Parkinson’s patients may be beneficial, from a therapeutic standpoint, to curb brain inflammation and reduce neuronal loss.

The findings were described in the study, “Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective,” published in the journal Nature Neuroscience.

Epigenetics is a field of research that studies how chemical modifications that affect the activity of certain genes come to occur, even though they are not encoded in a cell’s DNA. These chemical modifications, which either can promote or block the activity of certain genes, are added to specific regions of their DNA sequence by a group of specialized enzymes.

Although epigenetic modifications are thought to contribute to the onset and progression of Parkinson’s, “thus far, the epigenomes of patients with PD [Parkinson’s disease] remain largely unexplored, and epigenetic contributions to neuronal dysfunction in this disease are not well understood,” researchers wrote.

To investigate the impact these epigenetic modifications might have in Parkinson’s, researchers at the Van Andel Institute examined and compared the epigenetic profile of neurons isolated from patients with Parkinson’s to those of healthy people.

When they examined both types of neurons, they found that those isolated from people with Parkinson’s had a much higher number of chemical modifications associated with an increased activity of TET2, one of the genes that provides instructions to make an enzyme that is able to add these chemical modifications to a gene’s DNA sequence.

Increased activity of the TET2 gene led to the activation of genes involved in the reactivation of the cell cycle, which can destroy neurons, and in the generation of a strong immune response associated with inflammation.

To investigate if blocking the activity of TET2 could reduce neuronal loss and inflammation, researchers inactivated the gene in a mouse model of induced inflammatory neurodegeneration.

In these animals, a single dose of lipopolysaccharide (LPS), a bacteria-derived toxin, is used to trigger an immune response coupled with inflammation. This inflammatory process leads to the destruction of dopamine-producing neurons (those lost gradually over the course of Parkinson’s).

When researchers blocked the activity of the TET2 gene in these mice, they found that dopamine-producing neurons no longer were destroyed, and pro-inflammatory genes that normally would be active and trigger an excessive immune response were shut down.

The research team suggests that lowering the activity of TET2 in patients with Parkinson’s may be valuable therapeutically to reduce brain inflammation and prevent neuronal loss.

“Parkinson’s 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,” Viviane Labrie, PhD, said in a press release. Labrie is an associate professor at the Van Andel Institute and senior author of the study.

Labrie also noted that more research is needed before a therapeutic intervention based on TET2 can be developed. However, she also stated it is a promising new treatment avenue she and her team are exploring already.