by Yue Feng

Weakened synaptic development and synaptic plasticity, as a result of lacking the functional Fragile X protein (FMRP), underlies the intellectual disability in Fragile X Syndrome (FXS). Decades of investigation established the role of FMRP in binding its mRNA targets and regulating translation in response to neuronal and synaptic activity changes. Exciting discoveries on two receptors, mGluR5 and GABA, signaling in FXS animal models have led to promising therapeutic approaches based on variation of synaptic activity by mGluR5 antagonists and GABA agonists. However, clinical trials only achieved partial reverse of FXS phenotype. Thus, developing additional therapeutic strategies for treating the full spectrum of FXS symptoms are still pressing challenges.

The identification of genome-wide Fragile X protein (FMRP) target mRNAs by recent discoveries provides important clues for unraveling prevailing pathways underlying the genetic cause of FXS. Among the identified FMRP functional groups, mRNAs encoding the protein Cyclin-dependent kinase 5 (CDK5) and activators for this kinase are of particular interest, considering the central role of the CDK5 pathway in controlling brain development and synaptic plasticity, which displays marked overlap with Fragile X protein function. In fact, several CDK5 substrates phosphorylated in neurons by this kinase are FMRP targets as well, represented by the microtubule associated protein 1B (MAP1B). We have obtained data that CDK5 activators are dysregulated in the brain of Fmr1 KO mice.

CDK5 plays an important role in synaptic structure and plasticity, and overlaps the function of the Fragile X protein. In the brains of mice displaying Fragile X, these CDK5 activators do not function properly.

Using experimental systems and molecular tools recently established in our lab for studying CDK5 pathway function and regulation, this proposal offers a package of experimental plans based on molecular, genetics, and pharmacological approaches, aiming to break down whether and how CDK5 signaling is affected by the loss of FMRP. More importantly, taking the advantage of emerging CDK5 inhibitors developed against other brain disorders represented by Alzheimer’s disease and stroke, this proposal will provide the first evidence regarding CDK5 as a therapeutic target in correcting synaptic abnormalities and the mental impairment in FXS.