Oxidative stress plays a key role in cell dysfunction in a number of diseases, including amyotrophic lateral sclerosis (ALS). Our goals are to identify the roles of the transcription factor Nrf2 and its DNA binding sequence, the antioxidant response element (ARE) in ALS. Nrf2 and ARE are fundamental components in activating detoxification pathways, as demonstrated in Nrf2 knockout mice that are more sensitive to oxidative stress-inducing toxins and toxicants. The role of Nrf2-ARE in ALS initiation and progression will be investigated using transgenic mouse models, ARE-hPAP reporter or Nrf2 knockout mice, crossed with the ALS model SODG93A mice. SODG93A/ARE-hPAP reporter mice will identify the temporal and spatial distribution of oxidative stress, measured by hPAP activity, at varying stages of ALS. The SODG93A/NFf2 knockout mice will demonstrate the sensitivity of these mice to stress and subsequent motor neuron cell death involved in ALS progression. We will attempt to stimulate the protective Nrf2-ARE pathway with chemicals tert-butylhydroquinone or sulforaphane or infection (intramuscular injection) with an adenovirus-containing Nrf2 (Ad-Nrf2, previously shown to dramatically protect neuronal cells) to abrogate the motor neuron loss. Overall, we hope to utilize these transgenic mouse models to demonstrate the importance of Nrf2-ARE in depicting and preventing oxidative stress, as well as, promoting motor neuron survival during ALS disease progression. ? ?
| Kern, Julie C; Kehrer, James P (2005) Free radicals and apoptosis: relationships with glutathione, thioredoxin, and the BCL family of proteins. Front Biosci 10:1727-38 |
