Correcting Fragile X Syndrome by Inhibiting the Synaptic RNA-Binding Protein CPEB1
Joel Richter, PhD
Principal Investigator
Natalie Farny, PhD
FRAXA Postdoctoral Fellow
University of MA Medical School
Worcester, MA
2008-2011 Grant Funding: $170,000
Summary
The Richter lab is the foremost research group in the world in the study of CPEB, a protein critical for regulation of protein synthesis. With $170,000 in grants from FRAXA Research Foundation over 2008-2011, Dr. Joel Richter of the University of MA Medical School explored whether inhibitions of the CPEB may be a viable approach for treatment of Fragile X.
The Results
Udagawa et al., 2013, “Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology” showed that removing or reducing the CPEB1 protein in Fmr1(-/y) (Fragile X model) mice corrected multiple Fragile X–associated problems, including biochemical, morphological, electrophysiological, and memory/behavioral deficits, supporting the hypothesis that targeting CPEB1 can reverse key aspects of the disease.
November 2014: NIH awards Richter $9.5 million for Fragile X research center
The Science
CPEB and FMRP are two translational regulatory proteins found at postsynaptic and other sites in the brain. Thinking that a functional interaction between the two proteins might influence characteristics associated with the Fragile X Syndrome, we generated FMRP/CPEB double knockout mice (DKO). These animals, as well as wild type (WT), FMRP KO, and CPEB KO mice were subjected to a battery of behavioral tests. In addition, we tested brain tissue from the four genotypes for synaptic function and protein synthesis. We found that many behaviors typically considered to be Fragile X syndrome-associated in FMRP KO mice were corrected in the DKO animals. Moreover, the synaptic deregulation and aberrantly high protein synthesis found in FMRP KO mice were also corrected in the DKO animals.
These data suggest that CPEB might be a suitable target for therapies aimed at ameliorating the Fragile X Syndrome. We are investigating this possibility and working to understand the molecular basis of the FMRP-CPEB interaction.