Validation of the Transcriptional Repressor Bach1 as a Novel Target to Enhance Antioxidant Response Pathway and Block Neurodegeneration in Parkinson’s Disease

Target Validation, 2013

Objective/Rationale:
Bach1 is a transcriptional repressor, which is a protein that binds to a specific DNA site and prevents transcription of nearby genes. Bach1 is primarily localized to the nucleus and bound to antioxidant response elements (ARE) of a subset of genes. During disease conditions, levels of Bach1 increase significantly leading to inhibition of activity that causes oxidative stress, exaggerated inflammation and subsequent neurodegeneration. Our proposed study will provide new knowledge on whether antagonizing Bach1 in a toxicant-induced model of Parkinson’ disease (PD) is beneficial and will provide clues on inducing ARE response.

Project Description:
To validate the role of Bach1 in modulation of antioxidant response pathway and neurodegeneration, we will administer the parkinsonian neurotoxin MPTP in wild type and Bach1-null pre-clinical models. We will assess numbers of immunoreactive neurons, striatal dopamine and metabolites, markers of oxidative stress, and inflammation, and assess mRNA and protein levels for ARE genes in the ventral midbrain. These studies will establish how altering Bach1 expression could be beneficial against MPTP-induced dopaminergic neurodegeneration and provide crucial information on its role in modulating ARE signaling in PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently available therapeutics for PD only provide short-term symptomatic relief, but do not stop the disease progression. In this project, we will explore a novel approach to block dopaminergic neurodegeneration by activating the ARE pathway by silencing its repressor Bach1. This work may pave way for new neuroprotective strategies in PD.

Anticipated Outcome:
This study will provide important information on the relevance of Bach1 silencing in modulating ARE pathways and in neuroprotection in a pre-clinical model of PD. We expect that blocking the repressive effect of Bach1 will prevent key pathogenic processes that lead to dopaminergic neuron loss in PD, including oxidative and inflammatory stress. If the proposed studies are positive, they will suggest Bach1 inhibition as a novel target for therapeutic intervention to stop disease progression in PD.

FINAL OUTCOME

Bach1 is a protein that prevents production of other proteins by binding to the cell's genetic material, DNA. This protein is believed to play a role in the cell's response to oxidative stress, i.e., toxic effects of oxygen, and in neurodegeneration. To confirm this, we treated pre-clinical models with and without Bach1 with a toxic chemical that causes the loss of brain cells similar to that in Parkinson's disease (PD). Thus far, our studies have showed that the lack of Bach1 partially prevents both the loss of brain cells and the increase in signs of oxidative stress in the substantia nigra, a part of the brain involved in PD. Using another pre-clinical model with Parkinson's features, we observed fewer signs of inflammation in the substantia nigra in the absence of Bach1. In these models, genes responsible for the production of antioxidants, prevention of inflammation and production of energy are not suppressed, which provides neuroprotection. We are currently conducting additional studies to further confirm Bach1 as a novel neuroprotective target for Parkinson's disease.

November 2014