Nuclear RNA Binding Proteins in Neurodegeneration

A major public health challenge in our rapidly aging society is a progressively increasing population affected by neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Our long-term goal is to understand fundamental principles governing the formation and maintenance of the nervous system. We focus on investigating molecular and cellular mechanisms underlying neurodegenerative diseases, including tauopathy, TDP-43 and FUS proteinopathies. We have established cellular and animal models to study the post-transcriptional regulation of the human tau gene, with our sharp focus on the RNA binding protein (RBP) network regulating the expression of the human tau gene at the level of pre-mRNA splicing. We have also developed biochemical assays, cellular and animal models to understand molecular pathogenesis of dementia and motor neuron diseases associated with dysregulation of RNA binding proteins, including TDP-43 and FUS. Our recent data show that these nuclear RBPs translocate to mitochondria and elicit mitochondrial damage. Genetic studies reveal that altering expression of mitochondrial genes that interact with TDP-43 or FUS modify neurodegenerative phenotypes in animal models, indicating that mitochondrial defects are among disease-driving events in TDP-43 and FUS proteinopathies.