TET2 – A Master Switch to Turn off Parkinson Disease Symptoms

In a new study published in Nature Neuroscience, Dr. Viviane Labrie’s team from the Van Andel Institute has reported the discovery of a ‘master switch’ that can turn off inflammation and damage in neurons.

By Sahana Shankar, Ph.D. Candidate

Parkinson’s disease (PD) is a neurodegenerative disease that severely affects motor and non-motor functions due to the loss of dopaminergic neurons in the substantia nigra region of the brain. It causes progressively debilitating symptoms, affecting patients’ quality of life. An estimated 10 million people worldwide have PD. There is no current therapy available and most clinical interventions are focused on managing symptoms. However, huge strides have been made in understanding the pathology, identifying PD-biomarkers for early diagnosis, and delaying disease progression.

Epigenetic changes like DNA methylation have long been considered as master regulators which can turn on/off several sets of genes to modulate cell function. DNA methylation profiles are cell-type specific. Disease-based changes in epigenetic markers can alter cell functions and immune responses.

A new study focused on dissecting the changes in DNA methylation in PD patients. Looking at specific regions of the genome, from neurons isolated from the prefrontal cortex of PD patients, Dr. Viviane Labrie’s group found that enhancers were differentially methylated (mostly hypermethylated) compared to healthy controls. Enhancers typically activate genes and their hypermethylation may cause over-activation. To identify candidates that were upregulated due to enhancer disruption, they performed genome-wide Hi-C assays and discovered that the TET2 gene is a target of epigenetically altered enhancers.

Ten-eleven translocation (TET) enzymes catalyze the conversion of methyl groups on DNA to hydroxymethyl chains, mostly at enhancers. This epigenetic modification is important for gene expression and survival in cells. The TET2 gene has been identified as an immune response activator in the brain. However, it has a different function in inflamed neurons, based on previous studies.

To understand the role of TET2 enhancer dysregulation, they examined hydroxymethylcytosine levels in PD neurons by hydroxymethylated DNA immunoprecipitation sequencing and found a prominent increase. Transcriptome analysis of prefrontal cortical tissue and neurons showed that the TET2 transcript was elevated as well, suggesting that this upregulation may cause aberrant hydroxymethylation. Profiling of the TET2 gene for DNA methylation showed that enhancer was hypermethylated and the promoter was hypomethylated and changes in methylation correlated with the severity of PD.

TET2 depletion by shRNA in PD-neurons derived from patients and SH-SY5Y neuroblastoma cell line caused a significant hypomethylation at enhancers. The researchers investigated the epigenetic effect of TET2 loss in a mouse model in which neurodegeneration could be induced by injecting lipopolysaccharide, and observed reduced neurodegeneration and protection against loss of motor learning compared to WT mice. Tet2 knockdown in PD-model mice protected midbrain dopaminergic neurons from injury and behavioral motor defects. Transcriptomic analysis of WT and Tet2 KO mice revealed that TET2 loss can suppress inflammation-induced immune signaling pathways.

In summary, the study showed that enhancer dysregulation causes elevated levels of TET2 in PD patients which switches off the neuroprotective pathways and suppresses the immune system. This results in an inflammatory cascade and neurodegeneration. However, loss of Tet2 can confer protection against the inflammatory events and provides a new therapeutic avenue for PD. Transient reduction of Tet2 in PD patients may help recover from inflammatory attacks and sustained Tet2 loss may help alleviate PD symptoms. According to Dr.Labrie, “More work is needed before a TET2-based intervention can be developed, but it is a new and a promising avenue.”

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References

1. https://parkinsonsnewstoday.com/parkinsons-disease-statistics/
2. https://www.nature.com/articles/s41593-020-0690-y

Author

Sahana Shankar