What are the main symptoms of the Fragile X Syndrome?
It is the most frequent cause of inherited intellectual disability especially among boys because the mutated gene, FMR1, is located on the X chromosome. Nearly half of all children with FXS meet the criteria for a diagnosis of Autism Spectrum Disorders. It results in a spectrum of intellectual disabilities and physical characteristics. Individuals with FXS show several behavioral characteristics such as stereotypic movements, hyperactivity, hypersensitivity and social anxiety.
What are the existing clinical options for an FXS patient? Can this be improved?
Unfortunately, there are no cures for the underlying deficits of FXS. Currently, patients receive symptombased treatment medications that aim to minimize the secondary characteristics associated with FXS.
“We are very optimistic that our recent findings set the
basis for a novel pharmacological treatment for FXS.”
In past years, more than 40 clinical trials have been initiated and many have unfortunately been discontinued due to the absence of global improvement. It is therefore of utmost importance to identify new and efficient pharmacological treatment protocols for FXS and, at the same time, target behavioral interventions.
Do you think your results can lead to possible new strategies?
We are very optimistic that our recent findings set the basis for a novel pharmacological treatment for FXS. We have patented the peptide used in the Pasciuto et al. 2015 study, validated its efficacy in murine brain cells in vitro and in vivo, and we are currently taking this approach to the next phase by devising a series of experiments required for preclinical trials.
Did it come as a surprise that APP plays a role in FXS?
The first findings that APP levels are up-regulated in FXS came from the work of Westmark and Malter (PLoS Biol. 2007). One year later, we discovered that APP mRNA was regulated by the FMRP-CYFIP complex (Cell 2008). With the present study, we have now pinpointed a pathological role for non-amyloidogenic processing of APP, showed that the boost in sAPPα gives rise to the expression of APP and ADAM10, the α-secretase that generates sAPPα from APP. We have also found that this pathway goes awry in human cases of FXS, and shown that in the mouse model for FXS, blocking ADAM10 in early life may help to treat the disorder.
Can there be implications for Alzheimer research as well?
It was exciting to collaborate with the group of Bart De Strooper, a leader in the Alzheimer field. His knowledge has been instrumental for our project. At this stage our findings are more directed towards an amelioration of neurodevelopmental disorders hallmarked by an increase in sAPPα such as FXS and Autism.
Pasciuto et al., Neuron 2015