Excitotoxicity and oxidative stress have been implicated in a number of neurodegenerative disorders. However, how they cause neuronal death remains to be identified. My research is focused on investigating the mechanisms underlying excitotoxicity and oxidative stress as well as methods to protect neurons against these deleterious factors. My current research interests focus on two related topics.

1. Role of ubiquilin in neuronal cell survival

Ubiquilin is a presenilin-interacting protein and belongs to a type-2 ubiquitin-like protein family. Previous studies have shown that ubiquilin is strongly associated with neurofibrillary tangles in Alzheimer's disease (AD)-affected brains and can regulate the accumulation of presenilins (Mah et al. 2000). Recent data indicate that variants in ubiquilin gene increase the risk of the late-onset AD (Bertram et al. 2005). Based on these and other observations we hypothesize that ubiquilin plays an important role in AD pathogenesis and can regulate neuronal survival/death. We will utilize cultured neurons as a model system to characterize the expression of ubiquilin. We will determine whether overexpression of ubiquilin protects neurons against neuroexcitotoxin (such as glutamate), oxidative stress (such as H2O2) or b-amyloid1-42 peptide induced neurotoxicity. Furthermore, we will also use siRNA techniques and ubiquilin mutants as tools to examine the effect of knockdown of ubiquilin on neuronal cell survival/death as well as determine the role of each of the three distinguishable domains of ubiquilin (UbL, UbA and the central variable repeat region) in cell function.

2. Mechanism of alcohol-induced neuronal cell death
Alcohol is a potent neurotoxin and chronic consumption of alcohol has been associated with brain damage. Alcohol exposure during fetal development causes fetal alcohol syndrome characterized by a wide range of neuronal loss and functional abnormalities in the central nervous system. However, the exact mechanism of brain damage in alcoholics remains unknown. Neuronal excitation involving the excitatory glutamate receptors has been shown to be an important mechanism in alcohol-induced neuronal loss. Excitation resulting from stimulation of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA)-glutamate receptor, is known to cause increase of intracellular calcium and exacerbates the production of reactive oxygen and nitrogen species (ROS and RNS). We hypothesize that increase in intracellular ROS and RNS production following exposure of neurons to alcohol leads to DNA damage and activation of poly(ADP-ribose) polymerase (PARP), a DNA damage detection enzyme. Consequently, activated PARP will catalyze the synthesis of ADP-ribose polymer by consumption of large amount of intracellular NAD+ stores. NAD+ is an important molecule in neurons and depletion of NAD+ will lead neurons to die. Our research will focus on whether PARP activation is involved in alcohol-induced neuronal death, and if we find that it is involved, we will determine the signaling pathway regulating its activation and cell death.