A22 Genetic tools to validate and measure NRF2 in HD

Abstract

Huntington’s disease (HD) is an autosomal dominant inherited disease leading to significant neurodegeneration. The neuropathological characterisation of the disease is the loss of medium spiny neurons in the striatum. A hallmark of HD is the intracellular aggregation of huntingtin protein. Multiple mechanisms for neuronal cell death have been proposed including oxidative stress, mitochondrial dysfunction and impaired proteostasis. The Nrf2 (NF-E2-related factor 2) pathway has the potential to modulate all of these pathologic processes. Nrf2 is a transcription factor that binds to the ARE (antioxidant response element) and controls a powerful array of endogenous cellular antioxidant systems. Genes regulated through Nrf2 activation code for proteins that are direct antioxidants, enzymes that inactivate ROS (reactive oxygen species), produce reductive co-factors such as glutathione, combat endoplasmic reticulum stress, and modulate protein degradation pathways which affect protein turnover and homeostasis. Thus, Nrf2 is an attractive target for therapeutic intervention for neurodegenerative diseases. Previously, our laboratory demonstrated that transgenic mice with astrocyte-specific overexpression of Nrf2 (GFAP-Nrf2 mice) reduces chemical-mediated neurotoxicity in PD and HD models, as well as genetically-induced motor neuron degeneration in models of amyotrophic lateral sclerosis and Parkinson’s disease. The GFAP-Nrf2 mice were crossed with R6/2 mice. Overexpression of Nrf2 in astrocytes did not extend lifespan of the R6/2 mice. There was however some protection by astrocytic Nrf2 activation in the early stages of pathogenesis based on the rotarod, open field testing, and multiplex mRNA analysis in the GFAP-Nrf2/R6/2 compared to the R6/2 mice. On going studies are evaluating Nrf2 overexpression in neurons using transgenic mice and AAV-mediated gene delivery to the brains of R6/2 mice. Funded by the CHDI Foundation.