Correcting Fragile X Syndrome Deficits by Targeting Neonatal PKCepsilon Signaling in the Brain

FRAXA Research Foundation has made a 2017 grant of $90,000 to Probal Banerjee, PhD, at the College of Staten Island (CUNY). He is exploring a therapeutic strategy based on correcting abnormalities in the PKCepsilon signaling pathway in fragile X.

College of Staten Island
2017 FRAXA Research Grant
$90,000 over 2 Years
Banerjee team at College of Staten Island
$90,000 Grant
Alexandra Marsillo, Graduate Student
Probal Banerjee, PhD,
Principal Investigator
Tatyana Budylin,
FRAXA Fellow

The Reason for this Study

Fragile X syndrome (FXS) occurs due the silencing of the X-linked gene Fmr1, and it is known that the protein product (FMRP) of the Fmr1 gene controls expression of other proteins. However, it is unclear how the deficiency of FMRP leads to impairments. So far no mechanistic pathway has been found to link FMRP to FXS.

Discovery of FXS-associated Defects at the Molecular Level

Dr. Banerjee’s team is addressing this information gap by studying PKCe, which is one among the many gene products that are regulated by FMRP. By studying fragile X knockout (KO) mice, which lack FMRP, they have observed that PKCe expression is significantly suppressed in a hormone-secreting center of the brain, the hypothalamus, and the cognitive hub, hippocampus, which regulates hypothalamic activity. They also observed suppression of the sociability hormone oxytocin in the hypothalamus. Simultaneously, increased cell-surface localization of an excitation-causing protein, AMPAR, in the hippocampal nerve cells presumably increased anxiety in the KO mice.

Therapeutic Strategy for Permanent Correction of FXS-associated Defects

The scientists have attempted to compensate for suppressed PKCe signaling by treating the KO mice at an early age with the selective PKCe stimulator DCPLA. Quite strikingly, this resulted in a therapeutic correction of oxytocin expression in the hypothalamus, normalization of cell-surface AMPAR localization in the hippocampus, and correction of later-life hyper-anxiety and autistic-like social behavior deficits in adulthood! Thus, for the first time, this project brings the promise of elucidating a pathway that is compromised in the KO mice and uses a therapeutic strategy to correct the signaling pathway shortly after birth. This strategy is likely to correct early neurodevelopment in the brain and thereby afford a global, permanent correction of neuroconnectivity and behavior in the FXS mice.

The impression that fragile X mouse studies do not translate to human therapy is often based on treatments that are offered beyond the point of critical development when the brain can best be nudged to form the right connections. Therefore, it is highly important to conduct preclinical studies such as this during early brain development. Such studies will have a greater likelihood of eventually translating into successful human clinical trials.