Deciphering RNA Methylation in Regulating Neuronal Functions in Health and Disease

Type of Award: Catalyst
Date Awarded: June 2016
Award End Date: May 2018
Amount Awarded: $ 250,000.00
PI(s): Chuan He, PhD, UChicago; Yongchao Ma, PhD, NU;

Abstract: RNA methylation on N6-adenosine is emerging as a critical regulator of RNA function and metabolism. Neurological diseases, including spinal muscular atrophy (SMA), fragile X syndrome, and ALS, share pathogenic mechanisms involving defective RNA metabolism. However, the role of RNA methylation in mammalian neurons and neurological disorders has not been explored. We recently found that fragile X mental retardation protein (FMRP) binds specifically to consensus RNA methylation motifs. In addition, SMN (survival motor neuron) protein, whose expression is disrupted in SMA, interacts with FMRP; while SMA disease-associated SMN mutants can't interact. We hypothesize that FMRP and SMN read/interpret RNA methylation to regulate RNA localization, degradation and translation. Defects in these mechanisms are particularly exacerbated in polarized neurons with long neurites. Successful completion of the proposed studies will identify FMRP and SMN as new methylated RNA readers, and set the stage for functional investigation of RNA methylation in neurons and neurological diseases.