Several lines of evidence imply that autism, epilepsy, and schizophrenia may share some underlying brain abnormalities. Recent genetic studies suggest that mutations of Caspr2, gene product of CNTNAP2, increase the disease risk of these common manifestations. At the protein level, the role of Caspr2 in the rodent peripheral nervous system is established. In the human CNS, however, no information on the role of this protein and its neuronal location is thus far available. Recent studies suggest that Caspr2 is a key molecule in cell-cell interactions important for normal neuronal function and cortical development. To understand the structure of this protein and its functions in the human brain, we propose the following: 1) Study the three-dimensional structure of the extracellular domain of Caspr2. As the atomic structure of a protein drives its function, Caspr2 structure will enable us to improve our understanding of the biology of this neuronal protein and to predict how mutations linked to a disease state affect Caspr2 structure and function, thus setting the basis for future drug targets identification for epilepsy and autism. 2) Investigate the role of Caspr2 in hippocampal neurons and the biochemical and cellular consequences of mutations of human Caspr2 linked to ASD. Because mutations found in the human population affect the biological function of Caspr2, analysis of these mutations promises to yield critical insights into the neuronal anomalies that give rise to aberrations in neuronal connectivity, and may provide a basis for designing specific therapeutic interventions.

Public Health Relevance

Several lines of evidence indicate that autism, epilepsy, ADHD, Tourette syndrome, and schizophrenia share some common underlying brain abnormalities. Recent genetic studies suggest that mutations or copy number variation in the CNTNAP2 gene may cause some of these manifestations. The studies of the structure and the deleterious effects of the known mutations of Caspr2 (gene product of CNTNAP2) will help understanding the biology of this neuronal protein and predict how mutations linked to a disease state affect Caspr2 structure and function. Ultimately, these data will help researchers to develop therapeutic strategies to modify protein biosynthesis, processing, or adhesive properties of the partnering proteins to ameliorate these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH092906-01A2
Application #
8041617
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Asanuma, Chiiko
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2011-08-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$312,000
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Vieth, Joshua A; Das, Joy; Ranaivoson, Fanomezana M et al. (2017) TCR?-TCR? pairing controls recognition of CD1d and directs the development of adipose NKT cells. Nat Immunol 18:36-44
Ranaivoson, Fanomezana M; von Daake, Sventja; Comoletti, Davide (2016) Structural Insights into Reelin Function: Present and Future. Front Cell Neurosci 10:137
Rubio-Marrero, Eva N; Vincelli, Gabriele; Jeffries, Cy M et al. (2016) Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1. J Biol Chem 291:5788-802
Ulbrich, Lisa; Favaloro, Flores Lietta; Trobiani, Laura et al. (2016) Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system. Biochem J 473:423-34
Jackson, Verity A; Mehmood, Shahid; Chavent, Matthieu et al. (2016) Super-complexes of adhesion GPCRs and neural guidance receptors. Nat Commun 7:11184
Ranaivoson, Fanomezana M; Liu, Qun; Martini, Francesca et al. (2015) Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development. Structure 23:1665-1677
O'Sullivan, Matthew L; Martini, Francesca; von Daake, Sventja et al. (2014) LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5. Neural Dev 9:7
Savas, Jeffrey N; De Wit, Joris; Comoletti, Davide et al. (2014) Ecto-Fc MS identifies ligand-receptor interactions through extracellular domain Fc fusion protein baits and shotgun proteomic analysis. Nat Protoc 9:2061-74
Lee, Gum Hwa; Chhangawala, Zinal; von Daake, Sventja et al. (2014) Reelin induces Erk1/2 signaling in cortical neurons through a non-canonical pathway. J Biol Chem 289:20307-17
Falivelli, Giulia; De Jaco, Antonella; Favaloro, Flores Lietta et al. (2012) Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. Hum Mol Genet 21:4761-73