Accessible Requires Authentication Published by De Gruyter May 8, 2015

The cytoskeleton as a drug target for neuroprotection: the case of the autism- mutated ADNP

Illana Gozes
From the journal Biological Chemistry

Abstract

Fifteen years ago we discovered activity-dependent neuroprotective protein (ADNP), and showed that it is essential for brain formation/function. Our protein interaction studies identified ADNP as a member of the chromatin remodeling complex, SWI/SNF also associated with alternative splicing of tau and prediction of tauopathy. Recently, we have identified cytoplasmic ADNP interactions with the autophagy regulating microtubule-associated protein 1 light chain 3 (LC3) and with microtubule end-binding (EB) proteins. The ADNP-EB-binding SIP domain is shared with the ADNP snippet drug candidate, NAPVSIPQ termed NAP (davunetide). Thus, we identified a precise target for ADNP/NAP (davunetide) neuroprotection toward improved drug development.


Corresponding author: Illana Gozes, Department of Human Molecular Genetics and Biochemistry, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel, e-mail:

Acknowledgments

Support was provided by the AMN Foundation, Montreal Circle of Friend, Joe and Grace Alter, the Adams family, the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and The Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, ISF and the Israeli Ministry for Science Technology and Space. Professor Gozes is a Humboldt Award Recipient and a fellow at the Hanse-Wissenschftenkolleg, Germany.

References

Arens, J., Duong, T.T., and Dehmelt, L. (2013). A morphometric screen identifies specific roles for microtubule-regulating genes in neuronal development of P19 stem cells. PLoS One 8, e79796. Search in Google Scholar

Bassan, M., Zamostiano, R., Davidson, A., Pinhasov, A., Giladi, E., Perl, O., Bassan, H., Blat, C., Gibney, G., Glazner, G., et al. (1999). Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J. Neurochem. 72, 1283–1293. Search in Google Scholar

Ben-Ze’ev, A., Farmer, S.R., and Penman, S. (1979). Mechanisms of regulating tubulin synthesis in cultured mammalian cells. Cell 17, 319–325. Search in Google Scholar

Brenneman, D.E. and Gozes, I. (1996). A femtomolar-acting neuroprotective peptide. J. Clin. Invest. 97, 2299–2307. Search in Google Scholar

Brenneman, D.E., Hauser, J., Neale, E., Rubinraut, S., Fridkin, M., Davidson, A., and Gozes, I. (1998). Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides. J. Pharmacol. Exp. Ther. 285, 619–627. Search in Google Scholar

Brown, B.P., Kang, S.C., Gawelek, K., Zacharias, R.A., Anderson, S.R., Turner, C.P., and Morris, J.K. (2015). In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons. Neuroscience 290, 31–40. Search in Google Scholar

Chierchia, L., Tussellino, M., Guarino, D., Carotenuto, R., DeMarco, N., Campanella, C., Biffo, S., and Vaccaro, M.C. (2014). Cytoskeletal proteins associate with components of the ribosomal maturation and translation apparatus in Xenopus stage I oocytes. Zygote 1–14. Search in Google Scholar

Coe, B.P., Witherspoon, K., Rosenfeld, J.A., van Bon, B.W., Vulto-van Silfhout, A.T., Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E., et al. (2014). Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071. Search in Google Scholar

De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Cicek, A.E., Kou, Y., Liu, L., Fromer, M., Walker, S., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215. Search in Google Scholar

Dresner, E., Agam, G., and Gozes, I. (2011). Activity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: Deregulation in schizophrenia. Eur. Neuropsychopharmacol. 21, 355–361. Search in Google Scholar

Dresner, E., Malishkevich, A., Arviv, C., Leibman Barak, S., Alon, S., Ofir, R., Gothilf, Y., and Gozes, I. (2012). Novel evolutionary-conserved role for the activity-dependent neuroprotective protein (ADNP) family that is important for erythropoiesis. J. Biol. Chem. 287, 40173–40185. Search in Google Scholar

Fernandez-Montesinos, R., Torres, M., Baglietto-Vargas, D., Gutierrez, A., Gozes, I., Vitorica, J., and Pozo, D. (2010). Activity-dependent neuroprotective protein (ADNP) expression in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease. J. Mol. Neurosci. 41, 114–120. Search in Google Scholar

Furman, S., Steingart, R.A., Mandel, S., Hauser, J.M., Brenneman, D.E., and Gozes, I. (2004). Subcellular localization and secretion of activity-dependent neuroprotective protein in astrocytes. Neuron. Glia Biol. 1, 193–199. Search in Google Scholar

Furman, S., Hill, J.M., Vulih, I., Zaltzman, R., Hauser, J.M., Brenneman, D.E., and Gozes, I. (2005). Sexual dimorphism of activity-dependent neuroprotective protein in the mouse arcuate nucleus. Neurosci. Lett. 373, 73–78. Search in Google Scholar

Giladi, E., Hill, J.M., Dresner, E., Stack, C.M., and Gozes, I. (2007). Vasoactive intestinal peptide (VIP) regulates activity-dependent neuroprotective protein (ADNP) expression in vivo. J. Mol. Neurosci. 33, 278–283. Search in Google Scholar

Gkogkas, C.G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D.B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013). Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493, 371–377. Search in Google Scholar

Glowa, J.R., Panlilio, L.V., Brenneman, D.E., Gozes, I., Fridkin, M., and Hill, J.M. (1992). Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist. Brain Res. 570, 49–53. Search in Google Scholar

Gozes, I., Meltzer, E., Rubinrout, S., Brenneman, D.E., and Fridkin, M. (1989). Vasoactive intestinal peptide potentiates sexual behavior: inhibition by novel antagonist. Endocrinology 125, 2945–2949. Search in Google Scholar

Gozes, I., Glowa, J., Brenneman, D.E., McCune, S.K., Lee, E., and Westphal, H. (1993). Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene. J. Mol. Neurosci. 4, 185–193. Search in Google Scholar

Gozes, I., Iram, T., Maryanovsky, E., Arviv, C., Rozenberg, L., Schirer, Y., Giladi, E., and Furman-Assaf, S. (2014). Novel tubulin and tau neuroprotective fragments sharing structural similarities with the drug candidate NAP (Davuentide). J. Alzheimers Dis. 40 (Suppl 1), S23–36. Search in Google Scholar

Gozes, I., Yeheskel, A., and Pasmanik-Chor, M. (2015). Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer. J. Alzheimers Dis. 45, 57–73. Search in Google Scholar

Helsmoortel, C., Vulto-van Silfhout, A.T., Coe, B.P., Vandeweyer, G., Rooms, L., van den Ende, J., Schuurs-Hoeijmakers, J.H., Marcelis, C.L., Willemsen, M.H., Vissers, L.E., et al. (2014). A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46, 380–384. Search in Google Scholar

Hill, J.M., Hauser, J.M., Sheppard, L.M., Abebe, D., Spivak-Pohis, I., Kushnir, M., Deitch, I., and Gozes, I. (2007). Blockage of VIP during mouse embryogenesis modifies adult behavior and results in permanent changes in brain chemistry. J. Mol. Neurosci. 31, 183–200. Search in Google Scholar

Holtser-Cochav, M., Divinski, I., and Gozes, I. (2006). Tubulin is the target binding site for NAP-related peptides: ADNF-9, D-NAP, and D-SAL. J. Mol. Neurosci. 28, 303–307. Search in Google Scholar

Jarskog, L.F., Dong, Z., Kangarlu, A., Colibazzi, T., Girgis, R.R., Kegeles, L.S., Barch, D.M., Buchanan, R.W., Csernansky, J.G., Goff, D.C., et al. (2013). Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia. Neuropsychopharmacology 38, 1245–1252. Search in Google Scholar

Javitt, D.C., Buchanan, R.W., Keefe, R.S., Kern, R., McMahon, R.P., Green, M.F., Lieberman, J., Goff, D.C., Csernansky, J.G., McEvoy, J.P., et al. (2012). Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia. Schizophr. Res. 136, 25–31. Search in Google Scholar

Jaworski, J., Kapitein, L.C., Gouveia, S.M., Dortland, B.R., Wulf, P.S., Grigoriev, I., Camera, P., Spangler, S.A., Di Stefano, P., Demmers, J., et al. (2009). Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61, 85–100. Search in Google Scholar

Jouroukhin, Y., Ostritsky, R., Assaf, Y., Pelled, G., Giladi, E., and Gozes, I. (2013). NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport. Neurobiol. Dis. 56C, 79–94. Search in Google Scholar

Kushnir, M., Dresner, E., Mandel, S., and Gozes, I. (2008). Silencing of the ADNP-family member, ADNP2, results in changes in cellular viability under oxidative stress. J. Neurochem. 105, 537–545. Search in Google Scholar

Luo, S., and Rubinsztein, D.C. (2013). BCL2L11/BIM: a novel molecular link between autophagy and apoptosis. Autophagy 9, 104–105. Search in Google Scholar

Magen, I., and Gozes, I. (2013). Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: focus on davunetide (NAP). Neuropeptides 47, 489–495. Search in Google Scholar

Magen, I., and Gozes, I. (2014). Davunetide: Peptide therapeutic in neurological disorders. Curr. Med. Chem. 21, 2591–2598. Search in Google Scholar

Malishkevich, A., Amram, N., Hacohen-Kleiman, G., Magen, I., Giladi, E., and Gozes, I. (2015). Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer’s pathologies. Transl. Psychiatry 5, e501. Search in Google Scholar

Mandel, S. and Gozes, I. (2007). Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J. Biol. Chem. 282, 34448–34456. Search in Google Scholar

Mandel, S., Rechavi, G., and Gozes, I. (2007). Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis. Dev. Biol. 303, 814–824. Search in Google Scholar

Mandel, S., Spivak-Pohis, I., and Gozes, I. (2008). ADNP differential nucleus/cytoplasm localization in neurons suggests multiple roles in neuronal differentiation and maintenance. J. Mol. Neurosci. 35, 127–141. Search in Google Scholar

Matsuoka, Y., Gray, A.J., Hirata-Fukae, C., Minami, S.S., Waterhouse, E.G., Mattson, M.P., LaFerla, F.M., Gozes, I., and Aisen, P.S. (2007). Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer’s disease at early pathological stage. J. Mol. Neurosci. 31, 165–170. Search in Google Scholar

Matsuoka, Y., Jouroukhin, Y., Gray, A.J., Ma, L., Hirata-Fukae, C., Li, H.F., Feng, L., Lecanu, L., Walker, B.R., Planel, E., et al. (2008). A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. J. Pharmacol. Exp. Ther. 325, 146–153. Search in Google Scholar

Merenlender-Wagner, A., Pikman, R., Giladi, E., Andrieux, A., and Gozes, I. (2010). NAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse – a microtubule-deficient model of schizophrenia. Peptides 31, 1368–1373. Search in Google Scholar

Merenlender-Wagner, A., Shemer, Z., Touloumi, O., Lagoudaki, R., Giladi, E., Andrieux, A., Grigoriadis, N.C., and Gozes, I. (2014). New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia. Autophagy 10, 2324–2332. Search in Google Scholar

Merenlender-Wagner, A., Malishkevich, A., Shemer, Z., Udawela, M., Gibbons, A., Scarr, E., Dean, B., Levine, J., Agam, G., and Gozes, I. (2015). Autophagy has a key role in the pathophysiology of schizophrenia. Mol. Psychiatry 20, 126–132. Search in Google Scholar

Morimoto, B.H., Schmechel, D., Hirman, J., Blackwell, A., Keith, J., and Gold, M. (2013). A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 35, 325–336. Search in Google Scholar

Mosch, K., Franz, H., Soeroes, S., Singh, P.B., and Fischle, W. (2011). HP1 recruits activity-dependent neuroprotective protein to H3K9me3 marked pericentromeric heterochromatin for silencing of major satellite repeats. PLoS One 6, e15894. Search in Google Scholar

O’Roak, B.J., Vives, L., Fu, W., Egertson, J.D., Stanaway, I.B., Phelps, I.G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. (2012a). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622. Search in Google Scholar

O’Roak, B.J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B.P., Levy, R., Ko, A., Lee, C., Smith, J.D., et al. (2012b). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250. Search in Google Scholar

Oz, S., Ivashko-Pachima, Y., and Gozes, I. (2012). The ADNP derived peptide, NAP modulates the tubulin pool: implication for neurotrophic and neuroprotective activities. PLoS One 7, e51458. Search in Google Scholar

Oz, S., Kapitansky, O., Ivashco-Pachima, Y., Malishkevich, A., Giladi, E., Skalka, N., Rosin-Arbesfeld, R., Mittelman, L., Segev, O., Hirsch, J.A., et al. (2014). The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Mol. Psychiatry 19, 1115–1124. Search in Google Scholar

Pescosolido, M.F., Schwede, M., Johnson Harrison, A., Schmidt, M., Gamsiz, E.D., Chen, W.S., Donahue, J.P., Shur, N., Jerskey, B.A., Phornphutkul, C., et al. (2014). Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein. J. Med. Genet. 51, 587–589. Search in Google Scholar

Pinhasov, A., Mandel, S., Torchinsky, A., Giladi, E., Pittel, Z., Goldsweig, A.M., Servoss, S.J., Brenneman, D.E., and Gozes, I. (2003). Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res. Dev. Brain Res. 144, 83–90. Search in Google Scholar

Quraishe, S., Cowan, C.M., and Mudher, A. (2013). NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. Mol. Psychiatry 18, 834–842. Search in Google Scholar

Schirer, Y., Malishkevich, A., Ophir, Y., Lewis, J., Giladi, E., and Gozes, I. (2014). Novel marker for the onset of frontotemporal dementia: early increase in activity-dependent neuroprotective protein (ADNP) in the face of Tau mutation. PLoS One 9, e87383. Search in Google Scholar

Shiryaev, N., Jouroukhin, Y., Giladi, E., Polyzoidou, E., Grigoriadis, N.C., Rosenmann, H., and Gozes, I. (2009). NAP protects memory, increases soluble tau and reduces tau hyperphosphorylation in a tauopathy model. Neurobiol. Dis. 34, 381–388. Search in Google Scholar

Sudo, H. and Baas, P.W. (2011). Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases. Hum. Mol. Genet. 20, 763–778. Search in Google Scholar

Vandeweyer, G., Helsmoortel, C., Van Dijck, A., Vulto-van Silfhout, A.T., Coe, B.P., Bernier, R., Gerdts, J., Rooms, L., van den Ende, J., Bakshi, M., et al. (2014). The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism. Am. J. Med. Genet. C Semin. Med. Genet. 166C, 315–326. Search in Google Scholar

Vulih-Shultzman, I., Pinhasov, A., Mandel, S., Grigoriadis, N., Touloumi, O., Pittel, Z., and Gozes, I. (2007). Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J. Pharmacol. Exp. Ther. 323, 438–449. Search in Google Scholar

Yang, M.H., Yang, Y.H., Lu, C.Y., Jong, S.B., Chen, L.J., Lin, Y.F., Wu, S.J., Chu, P.Y., Chung, T.W., and Tyan, Y.C. (2012). Activity-dependent neuroprotector homeobox protein: a candidate protein identified in serum as diagnostic biomarker for Alzheimer’s disease. J. Proteomics 75, 3617–3629. Search in Google Scholar

Zamostiano, R., Pinhasov, A., Gelber, E., Steingart, R.A., Seroussi, E., Giladi, E., Bassan, M., Wollman, Y., Eyre, H.J., Mulley, J.C., et al. (2001). Cloning and characterization of the human activity-dependent neuroprotective protein. J. Biol. Chem. 276, 708–714. Search in Google Scholar

Zusev, M. and Gozes, I. (2004). Differential regulation of activity-dependent neuroprotective protein in rat astrocytes by VIP and PACAP. Regul. Pept. 123, 33–41. Search in Google Scholar

Received: 2015-4-4
Accepted: 2015-4-29
Published Online: 2015-5-8
Published in Print: 2016-3-1

©2016 by De Gruyter