RESEARCH TOPICS

One of the big tasks in neuroscience is to understand how a neuronal cell can store previous experience and change its output accordingly: the basis of learning and memory. Recent work has shown that a crucial contribution comes from autonomous protein expression in the periphery of the neuronal cell. Specific mRNAs are transported from the cell body to the axons and dendrites, where they are translated in a regulated manner. Our goal is to understand how this process contributes to learning and memory processes. For this aim, three broad questions have to be addressed: (i) Protein synthesis is typically cytoplasmic – how are the necessary components of the protein synthesis machinery transported to the dendrites/axons? In particular, how are the proper mRNAs selected. (ii) What triggers local protein synthesis? (iii) What downstream effects has this regulated translation?

Over the last five years, my lab has been studying the cause of the Fragile X syndrome. The Fragile X Syndrome is the most frequent cause of inherited mental retardation (1:2500 males, 1:4000 females) and is linked to the absence of the Fragile X Mental Retardation Protein FMRP. FMRP belongs to the family of RNA-binding proteins and has been implicated in translational control, but it is not understood how the absence of a translational regulator like FMRP could lead to a deficit in learning and memory and mental retardation. In fact, the study of the mental retardation protein FMRP touches all aspects of local translation at the synapses and therefore offers a major inroad into the understanding of this process.

1. Dendritic RNA/mRNA transport.
Synaptic protein synthesis is the final process of a multistep regulatory mechanism involving dendritic mRNA targeting and localization. For only few of these mRNAs it has been shown that cis-acting signals (3'UTR) mediates the targeting. We are focusing our interest on selected dendritic mRNAs among them FMR1 mRNA which encodes for the Fragile X Mental Retardation Protein, FMRP.

2. Regulation of local protein synthesis.
In order to study mRNA translation at the synapses, we have established an improved method for preparing synaptosomes from mouse brain. We have shown that protein synthesis occurs at the synapses and for some mRNAs it changes upon chemical stimulation (2). We have investigated the function of FMRP at synapses and show that FMRP acts as a translational repressor of specific mRNAs (3). We are currently elucidating how FMRP exerts this effect through characterization of the binding partners.