"Functional characterization of collybistin and gephyrin, key proteins involved in the development of inhibitory synapses"

• Grant number: 11/10348-9
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2011
• End date: January 31, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Andréa Laurato Sertié
• Grantee: Andréa Laurato Sertié
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Karina Griesi Oliveira ; Maria Rita dos Santos e Passos Bueno

Abstract

Collybistin and gephyrin are key proteins implicated in inhibitory synapse developmentand plasticity that cluster and localize inhibitory neurotransmitter receptors to the neuralpostsynaptic membrane. We have recently reported that collybistin and gephyrin interact with aprotein complex that controls translation initiation in eukaryotic cells (eIF3 complex), suggestingthat these proteins may also act as regulators of protein synthesis in neurons. However, thisnovel collybistin and gephyrin function must be confirmed in further studies. One of the aims ofthis research project is to verify if collybistin and gephyrin are indeed involved in thecontrol of translation initiation. In addition, we have recently started studying a Brazilianpatient with a deletion of the entire collybistin gene (ARHGEF9, Xq11.2) who show severe mentalretardation, epilepsy, and autistic behavior. In an attempt to explore pathophysiologicalmechanisms relevant for the development of the neurological impairment in this patient, whichmay also increase susceptibility to autism, this project also aims to verify if neural cells derivedfrom induced pluripotent stem cells of this patient show morphological, functional andmolecular changes (including alterations in protein synthesis). Finally, since this patient hasautism and collybistin seems to be involved in biological pathways previously associated with thisdisease, another aim of the present project is to estimate the contribution of ARHGEF9mutations to the genetic aetiology of autism. By reaching these three main objectives, thisproject intends to get a better understanding of collybistin and gephyrin functions, and ofbiological mechanisms underlying autism, which may allow the development of new and moreeffective treatments. (AU)