Molecular correlation between Alzheimer disease and Fragile X syndrome.

Proper synaptic contacts, trans-synaptic signalling, and structural remodelling are all essential aspects of synapse maturation, stabilization and function. In humans, abnormal spine density and/or shape are associated with many neurological disorders referred to as synaptopathies, indicating a link among spine morphogenesis, synaptic function and disease. The Fragile X Syndrome (FXS) is a well-characterized synaptopathy and it is the most common form of inherited intellectual disability (ID). Patients with FXS have cognitive deficits, behavioural disorders, anxiety and autistic-like features. The neurological defects are associated, at the cellular level, with an increased number of dendritic spines that appear long and thin. Unfortunately, no effective cure is available for FXS. At the molecular level, FXS is due to mutations or absence of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein expressed in several tissues with the highest level of expression in brain and gonads, the two organs mainly affected in patients with FXS. FMRP associates with messenger RNAs (mRNAs) and regulates their metabolism, i.e. transport, stability and translation. Loss of FMRP affects synaptic structure and plasticity possibly because several of the so-far identified FMRP targets include pre and post-synaptic proteins. One of the mechanisms through which FMRP inhibits translation of synaptic mRNAs is via the Cytoplasmic FMRP Interacting Protein 1 (CYFIP1) that acts as a non-canonical eIF4E-binding protein. Absence of FMRP increases the expression of theprotein under the control of the FMRPCYFIP1 translation regulatory complex. Importantly CYFIP1 also interacts with WAVE1 the main component of the Wave Regulatory Complex (WRC) that regulates actin polymerization. During my PhD thesis, in a collaborative study, we decided to investigatethe mechanism that regulates the presence of CYFIP1 in the two different complexes aiming at understanding if and how the two CYFIP1 complexes are required for proper spine morphology. We finally demonstrated that CYFIP1-dependent regulation of protein synthesis and actin remodelling isrequired for correct spine morphology in neurons. 
Among the proteins regulated by the CYFIP1- FMRP translation inhibitory complex is APP (Amyloid Precursor Protein). APP is a trans-membrane protein involvedin synapse formation, cell growth and differentiation. APP has been largely involved in the pathogenesis of Alzheimers Disease. During the second part of my PhD I studied the possible contribution of APP to FXS pathogenesis. We discovered that APP protein levels are higher in postmortem brains and cells from Fragile X patients. We have also shown that the increase in APP expression largely contributes to the FXS phenotype in mice.
To summarize, we discovered a new role for CYFIP1 as coordinatorof local protein synthesis and actin remodelling, two molecular pathways known to be dysregulated in Fragile X. Moreover, the CYFIP1-FMRP complex regulates APP expression a key protein in synaptic function. 
Altogether our work improves the understanding behind the exaggerated protein synthesis and the impaired synaptic function in FXS.

Keywords:Alzheimer disease, Neurodisorders

Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing, Genetics, Systems biology, Molecular and cell biology, Biochemistry and metabolism, Medical biochemistry and metabolism

Project type:PhD project