Mechanism and therapy of neurodegenerative diseases

My laboratory is working to understand the mechanism of neurodegeneration in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). ALS causes motor neuron degeneration, paralysis and death. FTD causes neurodegeneration in frontal and temporal cortex, resulting in degeneration of high brain functions, including altered personality, loss of executive ability, disabled social functions and regressive language skills. ALS and FTD are related because sometimes both diseases occur in the same patients and they share some cellular pathological features. We study these diseases by generating and analyzing animal models for these diseases. We are also developing RNAi therapy for these diseases.

We generate and use two types of animal models. One is gene overexpression models and the other is gene knockdown models. One overexpression model that we study is mice that express mutant human copper, zinc superoxide dismutase (SOD1) gene, which causes ALS. These mice develop ALS symptoms similar to humans. We hypothesize that mitochondrial damage and chaperone dysfunction contributes to motor neuron degeneration caused by mutant SOD1. Our experimental data support this hypothesis (Xu et al., 2004; Tummala et al., 2005). In addition to these mechanistic studies, we also use these mice to test new RNAi therapy strategies (Ding et al., 2003; Schwarz et al., 2006; Xia et al., 2006a).

For gene knockdown models, we use transgenic RNAi method that we have developed. We have demonstrated that transgenic RNAi knockdown of specific genes can recapitulate gene knockout phenotypes (Xia et al., 2006b). We have used transgenic RNAi to demonstrate that allele-specific silencing works in vivo (Xia et al., 2006a). Recently we have developed more sophisticated conditional knockdown strategies so that gene knockdown can be controlled spatially and temporally. We are using this transgenic RNAi strategy to target genes that are involved in ALS, FTD and Alzhermer’s disease.

In developing RNAi therapy strategies, we are testing two approaches. One is to express RNAi using viral vectors to silence disease genes. The other approach is being conducted in collaboration with Dr. Tariq Rana’s lab. We are testing delivering RNAi therapy using chemically modified siRNA that has enhanced stability. By these approaches, we hope that we will bring RNAi to clinical application for treatment of neurodegenerative diseases as well as other CNS disorders.