My laboratory is interested in defining the molecular pathways that regulate neuronal susceptibility to cell death, with specific focus on degeneration of substantia nigra dopaminergic neurons in Parkinson’s disease (PD). PD pathogenesis is thought to involve both genetic and environmental factors that interact in a complex manner centered on mitochondrial dysfunction, protein misfolding and/or aggregation, proteasome inhibition, and oxidative stress. However, the factors underlying selective vulnerability of substantia nigra dopaminergic neurons to these systemic processes are unknown. We currently use cell culture models and a combination of different approaches (molecular and cell biology, immunohistochemistry, in situ hybridization, imaging, biochemistry, and electrophysiology) to answer two specific questions:

(1) What is the role of cellular antioxidant defenses in PD pathogenesis?

The inducible expression of antioxidant enzymes and molecular chaperons in response to mild oxidative stress is regulated by Nrf2, a transcription factor that initiates the “programmed cell life” pathway in a number of different organs, including the liver, lung and brain. Interestingly, Nrf2 interacts with DJ-1 (one of several genes linked to the early onset, autosomal recessive form of PD), but the physiologic importance of this interaction is not yet established.

The goal of my laboratory is to define the role of Nrf2 and its downstream genes in protection from cell death induced by mitochondrial and proteasomal inhibitors. In addition, we plan to establish whether DJ-1-mediated protection from oxidative stress requires Nrf2 and to determine whether Nrf2 interacts with parkin, another gene linked to the autosomal recessive form of PD.

(2) What mechanisms link differences in membrane excitability to selective vulnerability of certain neuronal populations to degeneration?

Membrane excitability of an individual neuron is determined by the subset of ion channels it expresses on the plasma membrane. In addition to modifying neuronal activity, changes in the ion channel expression or function can affect neuronal survival, with both neuroprotection and neurotoxicity observed under different experimental conditions.

How do changes in ion channel activity translate into differential susceptibility to a range of cell death-inducing stimuli? What factors determine whether ion channel activation will be beneficial or detrimental to neuronal survival? To answer these questions, we are currently focusing on K_ATP channels, which link metabolic state of the cell to its membrane excitability.

In mouse models, the lack of K_ATP channels is detrimental for survival of cortical and hippocampal neurons exposed to acute ischemia, but beneficial for survival of SN dopaminergic neurons chronically exposed to MPTP (a parkinsonian neurotoxin). The goal of my laboratory is to establish how K_ATP channel activation affects neuronal survival after exposure to different metabolic stressors and to determine factors that shape the differential survival outcomes in different neuronal types.