We have been systematically pursuing the function of the RNA binding protein PTB as a key negative regulator of neurogenesis through its functional interplay with the REST complex. Via this regulatory axis, we demonstrate that depletion of PTB activates a large array of lineage-specific microRNAs and transcription factors, many of which have previously been shown to convert non-neuronal cells to functional neurons. This establishes the foundation to generate new neurons from endogenous non-neuronal cells not only in vitro but also in the brain. Indeed, we recently demonstrate the ability of the newly induced neurons to reconstitute the lost nigrostriatal pathway in a Parkinson’s disease model, leading to potent reversal of the disease phenotype.  Additional unpublished data, coupled with the existing literature information, suggest that the observed therapeutic benefit may result from multiple mechanisms, including acquisition of a new neurogenic program in a specific population of glia progenitors, inhibition of neuroinflammation, and restoration of impaired synapses in damaged neurons. These findings provide a broad foundation for developing RNA-based strategies to treat different forms of neurodegenerative diseases. 

Xiang-Dong Fu received his B.S. degree of Virology from Wuhan University in 1982. He was the first class of the CUSBEA (China-United States Biochemistry Examination and Application) for graduate training. He obtained his Ph.D. degree from Case Western Reserve University in 1988 and competed postdoctoral training at Harvard in 1988. In 1992, he joined the faculty at University of California, San Diego and rose through the rank. He became a Distinguished Professor of Cellular and Molecular Medicine in 2018 at UC, San Diego. Since January 2023, he joined Westlake University, Hangzhou, China as Chair Professor in RNA Biology and Regenerative Medicine.

Throughout his academic career, Dr. Fu has made four sets of discoveries: (1) By using partially purified spliceosome to raise a large panel of monoclonal antibodies, he discovered the first non-snRNP splicing factor SC35, which becomes a founding of the SR family of splicing regulators. He subsequently demonstrated that SR proteins function to commit pre-mRNA to the splicing pathway and elucidates a set of rules for SR proteins to regulate splice site selection during alternative splicing. (2) Dr. Fu’s group is also responsible for discovering the SRPK family of splicing kinases that are highly specific for SR proteins and elucidates a dedicated signaling pathway via these kinases to transduce growth factor signaling to the nucleus to regulate alternative splicing. (3) He discovered and characterized eRNAs expressed by active enhancers during transcriptional reprogramming, pioneered functional studies on a wide range of RNA binding proteins in diverse biological pathways, and elucidated their roles on chromatin in regulating transcription and mediating co-transcriptional RNA processing. (4) Dr. Fu’s team has uncovered a critical RNA program necessary and sufficient to trans-differentiate fibroblasts into functional neurons, and more recently, leveraged this discovery to directly convert glia cells into dopaminergic neurons in brain, leading to potent reversal of a Parkinson’s disease model. These findings establish a generalizable strategy for treatment of neurodegenerative diseases.

Dr. Fu’s contributions to biomedical research have been honored by selection or election as Searle Scholar (1994), Leukemia and Lymphoma Society Scholar (1997), AAAS Fellow (2010), the Ray Wu Society Award (2016), and Falling Walls Berlin for the Science Breakthroughs of the Year 2020.

 

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