Ecosystem
Beta Site
Session VI
AGPCRs shaping the nervous system
ADGRCs in glutamatergic synapse formation, maintenance and degeneration
Yimin Zou
Abstract
"ADGRCs (Celsr1-3) are components of the conserved planar cell polarity (PCP) pathway, which establishes and maintains cell and tissue polarity along the tissue plane in all tissues. Work from our lab showed that the PCP components, including ADGRC2 and ADGRC3, are localized in the developing and adult synapses and interact with synaptic scaffold proteins and glutamate receptors and are responsible for the formation and stability of the vast majority of glutamatergic synapses in the mammalian brain. Initial impairment of synaptic functions, which occurs early in Alzheimer’s disease, and subsequent massive loss of synapses are closely correlated with the decline of cognitive function. We showed that oligomeric Aβ binds to ADGRC3 on the same domain required for the interaction with Frizzled3, weakens their interaction and assists Vangl2 in disassembling synapses. Conditionally knocking out Ryk, required for Vangl2 function, protected synapses and preserved cognitive function in a mouse model for Alzheimer’s. Massive synapse loss in the prefrontal cortex is a hallmark of massive depressive disorder. Injection of low-dose ketamine, an antidepressant, can lead to acute (in several hours) and sustained (up to several weeks) antidepressive effects. Restoration of synaptic connections induced by low-dose ketamine has been found associated with the sustained antidepressive effects. We showed that ADGRC2 and ADGRC3 are required for the restoration of glutamatergic synapses in prefrontal cortical neurons of chronically stressed animals and their behavioral remission induced by low-dose ketamine. I will also present ongoing work on the signaling mechanisms of how ADGRCs regulate synapse formation, maintenance and plasticity."
About Yimin Zou
"I received Ph.D from University of California at Davis and San Diego in 1995 and then postdoctoral training from University of California, San Francisco in 2000. I was an assistant and then associate professor with tenure at the University of Chicago from 2000 to 2006 and moved to University of California San Diego as an Associate Professor in 2006. I became full professor in 2011 and Vice Chair of the Neurobiology Department at UC San Diego in 2012. I served as the Chair of the Neurobiology Department at UC San Diego from 2014 to 2017. My research focus is the mechanisms of neural circuit development, function and disease."
Yimin Zou on the web
Antibody-drug conjugates targeting CD97 in glioblastoma
Dimitris Placantonakis
Abstract
"Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Several adhesion G protein-coupled receptors (aGPCRs) have recently been shown to play critical roles in GBM biology. We showed that CD97 (ADGRE5), in particular, drives tumor growth via effects on GBM stem cell self-renewal and metabolism, but also has a therapeutically favorable expression pattern: it is highly expressed in all GBM specimens, but is absent from healthy brain tissue. To exploit this expression profile, we have developed antibody-drug conjugates (ADCs) targeting CD97, by screening a synthetic human antibody library. We initially tested the ADC using in vitro WST-8 viability assays in human GBM cell lines and cell types that lack CD97. We observed significantly lower LD50 values in patient-derived and U87 GBM cell cultures vs. CD97-lacking cells. We also found significantly lower LD50 values when treating human GBM cells with the ADC (0.6788 nM), as compared to control ADC targeting RSV glycoprotein F (19.964 nM). In vivo intratumoral administration of the ADC in patient-derived GBM xenografts in the brain of immunodeficient mice resulted in significant reduction of tumor growth and prolongation of survival of host mice. Collectively, these data suggest that ADCs targeting CD97 impair tumor growth in preclinical GBM models and are promising candidates for future clinical trials."
Authors & Affiliations
"Groff, Karenna; Donaldson, Hayley; Anderson, Sebastian; Pitti, Kiran; Wang, Shuai; Park, Christopher; Hattori, Takamitsu; Koide, Shohei; Placantonakis, Dimitris
New York University Grossman School of Medicine"
About Dimitris Placantonakis
"Dimitris Placantonakis is a neurosurgeon-scientist at NYU Grossman School of Medicine in New York. As a clinician, he specializes in surgical treatment of brain tumors. His laboratory studies oncogenesis in glioblastoma, the most common brain malignancy, and chromatin organization in human neural development. His group has been particularly interested in the role adhesion GPCRs play in glioblastoma biology and their therapeutic targeting."
Dimitris Placantonakis on the web
Adhesion G protein-coupled receptor latrophilin-3 (ADGRL3) modulation of dopaminergic neurotransmission
Nicole Perry-Hauser
Abstract
Only available for AGPCR 24 Attendees
Authors & Affiliations
"Nicole A. Perry-Hauser1,2, Arturo Torres Herraez1,2, Dan Lowes1,2, Ying Zhu1,2, Siham Boumhaouad1,3, Eugene V. Mosharov1,2,4, David Sulzer1,2,4, Christoph Kellendonk1,2, and Jonathan A. Javitch1,2
1Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032; 2Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032; 3 Physiology and Physiopathology, Faculty of Sciences, Mohammed V University, Rabat 1014, Morocco; 4Department of Neurology, Columbia University, New York, NY 10032"
About Nicole Perry-Hauser
"I am an associate research scientist endeavoring to build a productive, independent scientific research career in adhesion G protein-coupled receptor (aGPCR) biology. My long-term research interests involve resolving signaling pathways downstream of aGPCRs and establishing how/if these receptors’ adhesive properties influence signaling events, and in turn whether signaling impacts synapse formation and neuronal wiring. I initially became interested in GPCR signal transduction during my graduate training in the Department of Pharmacology at Vanderbilt University where I studied under the co-mentorship of Dr. Vsevolod V. Gurevich and Dr. Tina M. Iverson. I then pursued a postdoctoral research position under the mentorship of Dr. Jonathan A. Javitch in the Department of Psychiatry at Columbia University Irving Medical Center."