mRNA transport and local translation of actin-binding proteins in the Fragile X Syndrome

• Applicant: Professor Dr. Martin Korte
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325255501

Fragile X Syndrome (FXS) is the most common known monogenetic cause for autism. This genetically caused neuropsychiatric disorder is of high relevance in order to shed light on the importance of a balanced synaptogenesis and fine-tuning of neuronal. The most noticeable phenotype of FXS in the CNS is an apparent excess of immature dendritic spines, tiny protrusions on dendrites which represent the postsynaptic structures on the majority of neurons in the cortex. As knowledge about these structures increases, it becomes obvious that even subtle changes in synaptic function or development of spine morphology can result in severe cognitive abnormalities for a lifetime. This indicates that a deeper understanding of the molecular pathways involved in these disorders could not only provide us with potential cures but would eventually help to better understand the formation, function, and ever changing structure of synapses in the healthy central nervous system. FXS is characterized by the absence of the FMRP protein which binds mRNAs and indeed the altered spine density and morphology phenotype can be linked to a direct role of FMRP in activity-dependent mRNA transport, docking and local translation. In fact, translational dysregulation has recently been suggested to be a major factor in causing autism. Taken this into account, in our current project proposal we would like to use FXS as a model system to unravel crucial mechanisms of local dendritic protein synthesis and the specific function in synapse formation and maturation in the murine hippocampus in order to prepare the ground for translational applications. As the development, plasticity and maintenance of spine structure - whose impairment represents a hallmark of the FXS syndrome - is tightly linked to the actin cytoskeleton it is of high interest whether indeed one of the key features disturbed in FXS might be the crucial role of FMRP in regulating the transport and local translation of actin-binding proteins (ABPs). And indeed one of the most prominent features of FXS is the apparent spine morphology phenotype. Using different approaches like fluorescence in-situ hybridization and tools to visualize both mRNA transport and local protein synthesis we will be able to detect alterations in the localization of ABPs mRNAs in the course of FXS starting with earliest time points of synaptogenesis up to the mature state and correlate these changes to the spine phenotypes observed. These experiments will shed light on the role of locally translated APBs in synapse development and function in the healthy CNS as not much is known here either. As the experiments will be performed under basal conditions as well as upon induction of activity patterns known to reflect cellular processes crucial for learning and memory formation, we will therefore be able to contribute to a better and deeper understanding of the hallmark of FXS, a knowledge which is a pre-requisite for a rational treatment approach.

• DFG Programme: Research Grants