One of the major questions for neuroscience field is to understand the disease mechanisms underlying neurological and neurodegenerative disorders. Those diseases afflict millions of people worldwide, but so far almost no effective cure has been developed for these devastating disorders, partially due to our poor understanding of disease mechanisms. To tackle the disease mechanisms often relates to another key question in the field, the mechanisms underlying learning and memory, because impairment of learning and memory is often seen in many neurological and neurodegenerative diseases, including autism, schizophrenia, and Alzheimer’s disease. Since mouse shares over 90% gene similarity with human, to study chemical-induced mutant mice carrying learning and memory deficits or/and neurodegenerative phenotypes will great enhance our knowledge on the disease mechanisms and accelerate the speed in identification of novel therapeutic interventions. In addition, our disease-orientated research on these mutant genes also significantly deepens our understanding on these gene physiological functions. Our long-term goal is to combine molecular biology and mouse genetics to better understand the neurological and neurodegenerative disease mechanisms and bridge our basic research with therapeutic target discoveries. Current our research focuses include:
(1) The disease mechanisms underlying neurodegenerative disorders caused by RNA metabolism abnormalities.Fig.1. A chemical-induced mutant mouse (-/-) shows massive cerebellar neuron loss at 4 months of age, compared with wild type
littermate (+/+). We identified mutation in one of mouse U2 snRNA genes. The U2 snRNA is the basal component of pre-mRNA splicing machinery. The mutation results in global alternative splicing abnormalities and aberrant RNA specie accumulation. This mutant mouse not only provides definitive evidence directly link neurodegeneration and RNA metabolism abnormalities, but also offer us a unique model to study how dysfunction of RNA processing results in neurodegeneration, which is largely unknown in the field. The pictures are adopted from (YC Jia et al, Cell, 2012).
Recently, increasing evidence, including ours, suggested that dysfunction of RNA metabolism may play a key role in etiology of a range of neurodegenerative disorders, especially motor neuron disease. However, the basis of RNA metabolism in specific neuron types and their subcellular compartments during both physiological and pathological conditions is largely unknown. Currently, we focus on three RNA-binding proteins, IGHMBP2, TDP43, and FUS, and study how dysfunction of these genes results in motor neuron degeneration. In addition, we are interested to learn RNA species and their metabolism in specific cell type in the brain, including motor neurons, in different experimental paradigm and pathological conditions. To gain our understanding on these aspects, we combine neurobiology, molecular and cell biology, RNA biochemistry, high through-put sequencing, and mouse forward genetics.
(2) ER homeostasis regulation and ER-stress mediated neurodegeneration.
We are also very interested in the disease mechanisms underlying neurodegeneration caused by dysfunction of cellular organelles, especially endoplasmic reticulum (ER). ER has its essential roles in protein folding and in response to misfolded protein accumulation. Disruption of ER functions has been implicated in the etiology of many human diseases, including neurodegenerative diseases. Mouse forward genetics alone with other approaches described above are employed to identify key molecules in regulation of ER homeostasis at the entire animal level.
(3) Generation of new cell and animal models for neurodegenerative and neurological diseases.
We currently adopt CRISPR/CAS9 technique to do genome manipulation in human embryonic stem cells (hESCs) and entire animals. The hESCs carrying mutations found in neurological or neurodegenerative diseases are differentiated into different neuron types we are interested in. These cells serve as in vitro models for the diseases. Meanwhile, the mutations have been also introduced into animals, majorly mouse, to generate mammalian disease models. The combination of these approaches generating cell and animal models for human diseases will provide medium to transform our basic research into promising therapeutic interventions.