NFE2L1 is a protein that controls the expression of genes involved in the differentiation and survival of dopamine neurons. NFE2L1 levels are reduced in dopamine neurons in the brains of people with Parknison's disease (PD), and we recently found that a minor alteration of NFE2L1 can lower PD risk. These observations imply that neuron death in PD may result in part from a loss of the neuroprotective action of NFE2L1.
NFE2L1 can alleviate neuron death associated with alpha-synuclein accumulation and aggregate formation -- the hallmark pathology of Parkinson's -- in pre-clinical models of PD.
We will inject viruses designed to produce elevated levels of alpha-synuclein with or without NFE2L1-producing virus in the brains of Parkinson's models. In a second set of experiments, human PD brain tissue containing alpha-synuclein aggregates will be injected with or without NFE2L1-producing virus in the brains of PD models. We will analyze the models for evidence of motor abnormalities and to determine the degree of neuron loss and alpha-synuclein aggregate formation.
Impact on Diagnosis/Treatment of Parkinson's Disease:
The results of our study will shed light on the ability of NFE2L1 to reduce neurotoxicity resulting from alpha-synuclein aggregate formation or the spreading of alpha-synuclein aggregates throughout the brain. These insights will set the stage for developing PD therapies aimed at increasing NFE2L1 levels in the brain.
Next Steps for Development:
At the completion of this study, the next steps toward clinical application of our findings will be to screen for compounds that increase NFE2L1 levels in the brain, either by stimulating the protein's expression or by blocking the protein's destruction.