Davide Comoletti, DVM, PhD
PhD. Mario Negri Institute for Pharmacological Research
Milan, Italy, 1998
Child Health Institute of New Jersey
89 French Street, Floor 4 Room 4274
New Brunswick, NJ 08901
Office: (732) 235-9466; Lab: (732) 235-9858; Fax: (732) 235-9333
Autism spectrum disorder (ASD) and autism are both general terms for a group of complex disorders of brain development. Today, it is estimated that one in every 88 children is diagnosed with ASD, making it more common than childhood cancer, juvenile diabetes, and pediatric AIDS combined. Whereas the vast majority of cases of autism are idiopathic, a wealth of genetic studies point to the role of synaptic adhesion proteins in the pathogenesis of some form of the disease. Most of these synaptic proteins (neurexins, neuroligins, shanks, and many others) are important in controlling synaptic function, neuronal connectivity, and recognition patterns in the developing brain. Interestingly, some of these genes have also been implicated in the pathogenesis of epilepsy, schizophrenia, ADHD, and Tourette syndrome, suggesting that some of these disorders may share common molecular pathways.
In our lab we study the structural and molecular basis of synapse formation and connectivity in relation to ASD. We focus on the three-dimensional structure and cellular functions of several trans-synaptic adhesion molecules such as the neuroligins, neurexins, LRRTMs (see selected publication below). Besides these well-known proteins, other novel associating proteins have been recently discovered by us and by others and are currently under investigation in the lab. We use structural biology and cellular neuroscience to gain insights into how mutations of these proteins associate with autism and other common neurodevelopmental disorders.
A postdoctoral position in the area of Structural Biology is available. Prospective graduate students interested in structural biology projects are encouraged to contact the lab.
- O'Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S, Yates JR 3rd, Ghosh A. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron. 2012 73:903-10
- Miller MT, Mileni M, Comoletti D, Stevens RC, Harel M, Taylor P. The crystal structure of the α-neurexin-1 extracellular region reveals a hinge point for mediating synaptic adhesion and function. Structure. 2011 19:767-78.
- Comoletti D, Miller MT, Jeffries CM, Wilson J, Demeler B, Taylor P, Trewhella J, Nakagawa T. The macromolecular architecture of extracellular domain of alphaNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition. Structure. 2010 18:1044-53.
- Leone P, Comoletti D, Ferracci G, Conrod S, Garcia SU, Taylor P, Bourne Y, Marchot P. Structural insights into the exquisite selectivity of neurexin/neuroligin synaptic interactions. EMBO J. 2010 29:2461-71.
- de Wit J, Sylwestrak E, O'Sullivan ML, Otto S, Tiglio K, Savas JN, Yates JR 3rd, Comoletti D, Taylor P, Ghosh A. LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron. 2009 64:799-806.
- Comoletti D, Grishaev A, Whitten AE, Tsigelny I, Taylor P, Trewhella J. Synaptic arrangement of the neuroligin/beta-neurexin complex revealed by X-ray and neutron scattering. Structure. 15:693-705.
- Fabrichny IP, Leone P, Sulzenbacher G, Comoletti D, Miller MT, Taylor P, Bourne Y, Marchot P. Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion. Neuron. 2007 56:979-91.
- Comoletti D, Flynn RE, Boucard AA, Demeler B, Schirf V, Shi J, Jennings LL, Newlin HR, Südhof TC, Taylor P. Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. Biochemistry. 2006 45:12816-27.
- De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. J Biol Chem. 2006 281:9667-76.
- Boucard AA, Chubykin AA, Comoletti D, Taylor P, Südhof TC. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins. Neuron. 2005 48:229-36.
- Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Ellisman MH, Taylor P. The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci. 2004 24:4889-93.
- Comoletti D, Flynn R, Jennings LL, Chubykin A, Matsumura T, Hasegawa H, Südhof TC, Taylor P. Characterization of the interaction of a recombinant soluble neuroligin-1 with neurexin-1beta. J Biol Chem. 2003 278:50497-505.
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