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Damian Refojo "Needing Neddylation: a new post-translation pathway controlling spine development and maintenance "

Abstract :

The developmental processes orchestrating neuronal development and synaptogenesis not only explain the complexity of the wiring in the mature brain but also help understanding the biological substrate of neurodevelopmental disorders such as autism or mental retardation.
Most of the synaptic contacts are made between presynaptic axonal boutons and dendritic spines, postsynaptic microcompartments where membrane trafficking, calcium metabolism and protein synthesis and degradation are tightly controlled. Only in the post-synapse, more than 400 different proteins act in concert to mediate and control neural transmission. Therefore, a precise temporal and spatial control of protein synthesis and stability is required within spines. 
Ubiquitylation and other Ubiquitin-like proteins (UBLs) pathways like sumoylation, change the function, localization, partner interaction or stability of target proteins by triggering a covalent binding of the ubiquitin-like tags to the targets proteins. Both Ubiquitin and Sumo are post-translational modifications involved in a myriad of neuronal functions: neuronal survival, dendritic arborization, axonal growth, spine formation, synaptic pruning and trafficking of Glu receptors, among others. However, the putative role of other ubiquitin-like proteins on the CNS remains unknown. This is particularly surprising for the case of Nedd8 ("neural precursor cell expressed, developmentally down-regulated gene 8") an UBL sharing 80% homology with Ubiquitin that we have recently found to be highly expressed in the brain. Similarly to other UBLs, the neddylation pathway proceeds in the three classical biochemical steps of activation (E1), conjugation (E2) and ligation (E3). The different proteins involved in the Nedd8 conjugation pathway are highly expressed in neurons and more importantly the activity of the pathway change during developmental time windows where dendritogenesis and synaptogenesis take place. Thus we have intensely explored the role that neddylation exert on different aspects of dendritic development, spine formation and synaptic stability. These results as well as some of the mechanisms behind including the critical functional actions that neddylation exert on PSD95, the main scaffold protein of the postsynaptic density, will be discussed.

Selected publications

Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1"
Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom C, Schütz G, Nave K-A, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM. Science, (2011) 333:1903-190.

"Animal Models of Depression"
Refojo D and Deussing JM In "Neurobiology of Depression", Frontiers in Neuroscience Series, CRC Press, Editor: Francisco Lopez-Muñoz. (2011)
"CRH signaling: molecular specificity for drug targeting in the CNS"

Refojo D, Holsboer F.
Ann N Y Acad Sci, (2009), 1179:106-19.
"CRH activates ERK1/2 MAPK in specific brain areas"
Refojo D, Echenique C, Müller MB, Reul JMHM, Deussing J, Wurst W, Sillaber I, Paez-Pereda M, Holsboer F, Arzt E.
Proc Natl Acad Sci, (2005) 102:6183-6188.

"Increased splenocyte proliferative response and cytokine production in β-endorphin deficient mice"
Refojo D, Kovalovsky D, Young JI, Rubinstein M, Reul JMHM, Holsboer F, Low M, Arzt E.
Journal of Neuroimmunolgy, (2002) 131: 126-134.

Scientific focus :

2009-Present:    Max Planck Junior Group Leader
Molecular Neurobiology
Max Planck Institute of Psychiatry
2005-2009: Post-doctoral Fellow
Molecular Neurogenetics Research Group.
Max Planck Institute of Psychiatry.
18.09.2008 Dr. Damian Refojo becomes Independent Junior Research Group Leader at the Max Planck Institute of Psychiatry

Francoise Coussen de l'IINS