Caspr2 as an autism candidate gene: a proteomic approach to function &structure.

Summary

Principal Investigator: Davide Comoletti
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2011-08-01 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation
    Giulia Falivelli
    Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
    Hum Mol Genet 21:4761-73. 2012
  2. pmc LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5
    Matthew L O'Sullivan
    Neurobiology Section, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA
    Neural Dev 9:7. 2014

Detail Information

Publications2

  1. pmc Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation
    Giulia Falivelli
    Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
    Hum Mol Genet 21:4761-73. 2012
    ..Our data support a complex genetic architecture in which multiple distinct risk factors interact with others to shape autism risk and presentation...
  2. pmc LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5
    Matthew L O'Sullivan
    Neurobiology Section, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA
    Neural Dev 9:7. 2014
    ..In this study, we tested two hypotheses regarding LPHN3 function: (1) LPHN3 regulates synaptic transmission by modulating probability of release; and (2) LPHN3 controls synapse development and the abundance of synapses...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Proliferation, Specification &Brain Function
    MARGARET ELIZABETH ROSS; Fiscal Year: 2013
    ..This Program tackles this complexity through the combined efforts of 4 Pis using cutting edge approaches to the elucidation of how developmental signals regulate fate and output of these critically important neurons. ..
  3. Washington University Intellectual and Developmental Disabilities Research Center
    John N Constantino; Fiscal Year: 2013
    ..WUIDDRC will stimulate advances by creating a collaborative, interdisciplinary environment that will accelerate research to directly impact children with intellectual and developmental disabilities. ..
  4. IDDRC at Children's Research Institute
    Vittorio Gallo; Fiscal Year: 2013
    ..abstract_text> ..
  5. Baylor Intellectual and Developmental Disabilities Research Center
    Huda Y Zoghbi; Fiscal Year: 2013
    ..abstract_text> ..
  6. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  7. Interdisciplinary center of excellence for the study of pain and sensory function
    Ian D Meng; Fiscal Year: 2013
    ..Completion of these Aims will develop the research careers of a multidisciplinary group of junior investigators, and establish the core facilities and equipment necessary to constitute a competitive research center. ..
  8. Novel regulatory network involving non-coding role of an ASD candidate gene PTEN
    Deyou Zheng; Fiscal Year: 2013
    ..Our findings will be important for understanding the role of non-coding RNAs and pseudogenes in neuropsychiatric disorders, both of which may help explain disease-associated SNPs and CNVs in non-coding regions of the human genome. ..
  9. Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry
    Irwin M Chaiken; Fiscal Year: 2013
    ..Overall, the Program will provide a broad-based research infrastructure to identify new paths for the discovery of preventive and therapeutic agents that block HIV-1 Env function. ..
  10. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  11. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  12. NMR AND COMPUTATIONAL STUDIES OF BIOMOLECULES
    Gerhard Wagner; Fiscal Year: 2013
    ..We anticipate that the proposed research will continue to advance the capabilities of NMR for structural biology. ..
  13. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  14. Center for Biomedical Research Excellence in Pathogen-Host Interactions
    Stephen B Pruett; Fiscal Year: 2013
    ..We expect the combined reductionist and global approach in this COBRE to produce significant progress in research on these pathogens. ..
  15. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  16. EINSTEIN AGING STUDY
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  17. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  18. PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDS
    Dennis A Dougherty; Fiscal Year: 2013
    ..The knowledge generated from these studies will be very valuable to efforts to develop new pharmaceuticals to address the many neurological disorders associated with malfunctions of the Cys-loop receptors. ..
  19. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  20. Dopamine Transporter Regulation by Endocytosis
    Alexander D Sorkin; Fiscal Year: 2013
    ..The proposed research will use a combination of the state-of- the-art quantitative cellular imaging, including electron microscopy, and mass-spectrometry. ..
  21. Control of synapse formation and maturation by astrocytes
    Cagla Eroglu; Fiscal Year: 2013
    ....
  22. CANCER CENTER SUPPORT GRANT
    Nancy E Davidson; Fiscal Year: 2013
    ..abstract_text> ..