Study Rationale:
Genes can be switched on or off by proteins that add and remove chemical modifications to DNA. We and others have shown that the chemical modification of genes important for neuronal survival and immune regulation is altered in Parkinson’s disease (PD). Furthermore, we find that a protein called TET2 mediates these modifications — and that when TET2 activity is lost, pre-clinical models become resistant to chemical insults that normally lead to PD-like neuronal death.
Hypothesis:
We hypothesize that abnormal activation of TET2 causes changes in gene regulation that lead to the development of PD. We also predict that deactivating TET2 will inhibit the PD-like accumulation of abnormal proteins in the brains of pre-clinical models.
Study Design:
We will first examine the brains of people with PD to determine how changes in gene activity correlate with the alteration of DNA modifications that we have previously detected. Second, we will examine whether deactivation of TET2 can protect pre-clinical models against the accumulation of abnormal proteins that cause neuronal death and abnormal inflammation in the brain.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our work can identify novel ways of treating PD that will prevent the worsening of the symptoms once a patient has been diagnosed.
Next Steps for Development:
Once we determine which genes are affected by changes in DNA modification in PD, we will design strategies to counteract these alterations. In addition, once we validate the neuroprotective potential of deleting TET2 in a second model, we will move onto identifying drugs or interventions for deactivating TET2.