Funded Studies
Objective/Rationale:
Oxidative stress and damage are well-known contributors in the pathogenesis of Parkinson’s disease (PD). To combat oxidative damage, transcription factor Nrf2 increases cellular production of antioxidants. However, transcriptional inhibitors Bach1 and Bach2 interfere with Nrf2 function, thereby preventing the production of antioxidant enzymes and cellular defenses against toxicity. The aim of this study is to quantitatively assess the extent by which inhibition of Bach1 or Bach2 will protect against PD-associated toxicity.
Project Description:
To examine potential protective effects of Bach1 or Bach2 inhibition, researchers will treat pre-clinical models with a genetic ablation of Bach1 or Bach2 or with MPTP, a toxin that mimics dopaminergic neuron loss similar to that observed in PD. They will evaluate dopaminergic neuron viability, antioxidant enzyme production, gliosis (measurement of central nervous system damage), inflammation, oxidative stress, apoptosis (programmed cell death) and pathological protein accumulation to identify potential differences between genetically modified models. Researchers hope to identify the extent of neuronal protection and the reduction of oxidative stress that would result from inhibition of Bach1 or Bach2.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current therapies for PD reduce symptoms, but do not prevent progressive neurodegeneration. Mechanisms to promote antioxidant production would ensure better treatments and quality of life for those with PD. This study will provide a new therapeutic target that will limit progressive neurodegeneration by promoting antioxidant production.
Anticipated Outcome:
Researchers anticipate to show that blocking Bach1 and Bach2 will substantially augment Nrf2 activity, promote antioxidant production and protect dopaminergic neurons against toxicity. If this study supports this hypothesis, it would support inhibition of Bach1 and/or Bach2 as a treatment for PD.
Final Outcome
Proteins Bach1and Bach2 prevent the production of antioxidants -- molecules that mitigate toxic effects of oxygen -- leaving the cell defenseless against changes that occur in Parkinson's disease (PD). To examine whether turning off Bach1 or Bach2 would be therapeutic in Parkinson's, we created pre-clinical models of Parkinson's that lack one of these proteins. We hypothesized that the lack of Bach1 or Bach2 would translate into increased antioxidant levels and protect brain cells from damage. We have measured the function of dopamine-producing brain cells, which play a key role in Parkinson's, and are currently analyzing these measurements. We have also measured antioxidants in the substantia nigra, a part of the brain that contains dopamine-producing cells. We will continue to measure total levels and production of antioxidant proteins in several types of brain cells. In the future, we will determine the number of surviving brain cells in our models as well as the extent of oxidative stress -- the effect of toxic forms of oxygen -- as well as the response of other brain cells to the death of nerve cell in the substantia nigra. Based on our findings, we will determine whether the lack of Bach1 or Bach2 is neuroprotective.
November 2014