~90% of a neuron’s proteome resides in dendrites, axons and synapses, where demand for protein turnover is constant. Coordination between synthesis and degradation, protein turnover, sculpts the molecular architecture of a neuron and is necessary for brain development and plasticity. In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects several molecular and cellular pathological hallmarks of FXS. Furthermore, pharmacological or targeted genetic reduction of proteasome activity significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1-/y mouse. Together, these results identify excessive activation of the UPS pathway in Fmr1-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention. Importantly, several mutations that alter UPS function have been linked to autism, intellectual disability and epilepsy, I will also be discussing preliminaty data addressing how dysfunction in UPS is relevant to other neurodevelopmental disorders.

In the last two decades, the term synaptopathy has been largely used to underline the concept that impairments of synaptic structure and function are the major determinants of brain disorders. However, the multifactorial origin of tbrain disorders indicates the additional, key contribution of environmental factors. Among these, activation of the immune system is emerging as a risk factor for brain diseases, and in particular neurodevelopmental disorders. In my talk, I will provide evidence pointing to the concept that altered cross talk between the immune and nervous system, especially during development, may heavily impact formation and function of synaptic contacts. These evidence lead to the novel concept of “immune- synaptopathies", dysfunctions of the immune system affecting synaptic components and thus resulting in defective brain trajectories.

Tau is an axonal microtubule binding protein that gets phosphorylated and resorted into the somatodendritic compartment upon exposure of neurons to different stressors (hyperactivity, temperature, mechanical stress). In extreme “stress” scenarios, such as in Alzheimer’s disease and Tauopathies, highly phosphorylated Tau is permanently resorted and aggregates intra-neuronally into small oligomers and larger amyloid-like fibrils. The function of this resorting is unclear and mostly interpreted as pro-pathological because of its neuropathological association with disease. However, detachment of phosphorylated Tau from microtubules and its dendritic resorting also allows Tau to be present and interact with pre- and post-synapses. In my talk, I will discuss the (patho)physiological roles of Tau in synaptic compartments and present some of our recent data suggesting Tau effects on post-synaptic density function and assembly.