Neurobiology of autism gene products: towards pathogenesis and drug targets
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The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.
The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.
Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.
The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.
ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.
KeywordsAutism spectrum disorders Autism genetics Dendritic protein synthesis Autism drug targets Neurexin Neuroligin SHANK CNTNAP2 PTEN Fragile X syndrome mouse models
Authors of this review were supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant P7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and from Autism Speaks, resulting in a total of €29.6 million. N.B. was supported by the European Commission EUROSPIN and SynSys Consortia (FP7HEALTHF22009241498, FP7HEALTH F22009242167). D.D.K. is a recipient of a fellowship of the Alexander von Humboldt Foundation and a Marie Curie International Reintegration Grant of the European Commission. Research is further supported by the Deutsche Forschungsgemeinschaft (DFG, BO1718/4-1 to T.M.B.) and by the Baustein program of Ulm University (L.SBN.0081 to M.J.S.).
Conflict of interest
No conflicts of interest are reported.
- Anderson GR, Gal T, Xu W, et al (2012) Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. doi: 10.1073/pnas.1216398109/-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1216398109
- Boccuto L, Lauri M, Sarasua SM, et al (2012) Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Hum Genet 1–7. doi: 10.1038/ejhg.2012.175
- Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene–environment interactions. Dialogues Clin Nuerosci 14:281–292Google Scholar
- Denayer A, Van Esch H, de Ravel T, et al (2012) Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol 14–20. doi: 10.1159/000339119
- Du Y, Weed SA, Xiong W et al (1998) Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons. Mol Cell Biol 18:5838–5851PubMedCentralPubMedGoogle Scholar
- Dudanova I, Tabuchi K, Rohlmann A, Missler M (2007) Deletion of neurexins does not cause a major impairment of axonal pathfinding or synapse formation. 274:261–274. doi: 10.1002/cne
- Ey E, Yang M, Katz a M, et al (2012) Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4. Genes Brain Behav 928–941. doi: 10.1111/j.1601-183X.2012.00849.x
- Fraser MM, Bayazitov IT, Zakharenko SS, Baker SJ (2008) Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151:476–488. doi: 10.1016/j.neuroscience.2007.10.048 PubMedCentralPubMedGoogle Scholar
- Hanssen AMN (1995) Syndrome of the month Cowden syndrome. 117–119Google Scholar
- Herman GE, Butter E, Enrile B, et al (2007) Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. 593:589–593. doi: 10.1002/ajmg.a
- Jacquemont S, Curie A, des Portes V, et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra1. doi: 10.1126/scitranslmed.3001708
- Kano M, Ohno-shosaku T, Hashimotodani Y, Uchigashima M (2009) Endocannabinoid-mediated control of synaptic transmission. 309–380. doi: 10.1152/physrev.00019.2008
- Lesche R, Groszer M, Gao J, et al (2002) Cre/loxP-mediated inactivation of the murine PTEN tumor suppressor gene. 149:148–149. doi: 10.1002/gene.10036
- Naisbitt S, Kim E, Tu JC, et al (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and Cortactin University of North Carolina at Chapel Hill. 23:569–582Google Scholar
- Phelan K, McDermid HE (2011) The 22q13.3 deletion syndrome (Phelan-McDermid Syndrome). Mol Syndromol. 186–201. doi: 10.1159/000334260
- Spooren W, Lindemann L, Ghosh A, Santarelli L (2012) Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharmacol Sci 1–16. doi: 10.1016/j.tips.2012.09.004
- Takeuchi K, Gertner MJ, Zhou J, et al (2013) Dysregulation of synaptic plasticity precedes appearance of morphological defects in a PTEN conditional knockout mouse model of autism. doi: 10.1073/pnas.1222803110/-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1222803110
- Verpelli C, Schmeisser MJ, Sala C, Boeckers TM (2012) Synaptic plasticity: scaffold proteins at the postsynaptic density. 970:29–62. doi: 10.1007/978-3-7091-0932-8