Autism, Schizophrenia and Alzheimer’s Disease : a common thread from neuropeptides to brain regulating genes

Abstract

Our original cloning of the gene coding for vasoactive intestinal peptide (VIP) (Bodner, Fridkin & Gozes, 1985), led to the identification of VIP’s involvement in synapse formation and neuroprotection, through our discoveries of activity-dependent neurotrophic factor (ADNF) (Brenneman & Gozes, 1996) and activity- dependent neuroprotective protein (ADNP) (Bassan et al., 1999; Zamostiano et al., 2001). To precisely delineate VIP and ADNP activities in the whole animal, we established transgenic animals, showing that manipulating VIP content impacts cognition in the mouse (Gozes et al., 1993). As for mouse ADNP, complete knockout results in severe neuronal tube closure defects and embryonic death at the time of neural tube closure (Pinhasov et al., 2003). ADNP haploinsufficient mice survive and show cognitive and social deficiencies, with pathologies resembling autism (Malishkevich et al., 2015) and Alzheimer’s disease (Vulih-Shultzman et al., 2007). Delineating the mechanism of action of ADNP, we discovered binding to the SWI/SNF chromatin remodeling complex and heterochromatin protein 1 alpha, and direct interaction with specific gene promoters (e.g. the major risk gene for Alzheimer’s disease, apolipoprotein E) (Mandel & Gozes, 2007; Mandel, Rechavi & Gozes, 2007). We have further discovered interactions with proteins associated with RNA splicing (Schirer et al., 2014), as well as with proteins regulating translation, like eukaryotic initiation factor 4E (Eif4e) (Malishkevich et al., 2015). In the cell cytoplasm, ADNP further interacts with the autophagy mechanism, binding to microtubule associated protein 1 light chain 3 (LC3) (Merenlender-Wagner et al., 2015) and to microtubule end binding proteins (EBs) (Oz et al., 2014).