Davunetide: Peptide therapeutic in neurological disorders.
Curr Med Chem. 2014;21(23):2591-8.
Magen I, Gozes I.
Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Director, The Adams Super Center for Brain Studies and The Edersheim Levie-Gitter fMRI Institute; Head, the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. [email protected]
This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.
As Alzheimer’s disease progresses, it kills brain cells mainly in the hippocampus and cortex, leading to impairments in “neuroplasticity,” the mechanism that affects learning, memory, and thinking. An independent study, led by Prof. Illana Gozes and published in Molecular Psychiatry(1), revealed a nerve cell protective molecular target that is essential for brain plasticity for NAP and ADNP. This discovery offers a new target for drug design and an understanding of mechanisms of cognitive enhancement.
The new finding is based on Prof. Gozes’ discovery of NAP, a snippet of the protein essential for brain formation, ADNP. As a result of this discovery, a drug candidate that showed efficacy in mild cognitive impairment patients, a precursor to Alzheimer’s disease, is being developed. NAP protects the brain by protecting the microtubules – cellular cylinders that provide “railways and scaffolding systems” to move biological material within cells and provide a cellular skeleton. Microtubules are of particular importance to nerve cells, which have long processes and would otherwise collapse. In neurodegenerative diseases like Alzheimer’s, the microtubule network falls apart, hindering cellular communication and cognitive function.
Clinical studies have shown that Davunetide (NAP) protects memory in patients suffering from mild cognitive impairment preceding Alzheimer’s disease. While the mechanism was understood in broad terms, the precise molecular target remained a mystery. Now, in light of the new research, the mechanism is much clearer paving the path to further progress.
NAP/ADNP were shown to target microtubule end binding proteins (EBs), promoting microtubule growth at the tips of the tubes (“rails”). The NAP/ADNP structure allows the binding to the tip of the growing microtubule, the emerging “railway,” through these specific microtubule end-binding proteins, which adhere to microtubules a bit like locomotors to provide for growth and forward movement, while the other end of the microtubule may to be disintegrating. These growing tips enlist regulatory proteins that are essential for providing plasticity at the nerve cell connection points, the synapses.
The Gozes group has now revealed that ADNP through its NAP motif binds the microtubule end binding proteins and enhances nerve cell plasticity, providing for brain resilience. The group then discovered that NAP further enhances ADNP microtubule binding.
Microtubules are also involved in the autophagy pathway, a process preserving the balance between synthesis, degradation and recycling of cellular components. The microtubule associated protein 1 light chain 3 (LC3) is a key protein that governs the autophagy pathway. The Gozes group showed that ADNP co-immunoprecipitated with LC3B and that NAP enhances this association(2). These findings implicate protection of the autophagy process by the NAP motif of ADNP, as verified in a cellular system of Parkinson’s disease(3).
These mechanistic findings are coupled to the original finding of ADNP function as part of an essential chromatin remodeling complex. It is hoped that the recent discoveries will help move Davunetide (NAP) and related compounds into further clinical trials, increasing the potential of future clinical use. Prof. Gozes is continuing to investigate ADNP(4, 5) and microtubule-peptide protection(6, 7) to better understand their protective properties in the brain.
- Oz, S., Kapitansky, O., Ivashco-Pachima, Y., Malishkevich, A., Giladi, E., Skalka, N., Rosin-Arbesfeld, R., Mittelman, L., Segev, O., Hirsch, J.A., and Gozes I. 2014. The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Mol Psychiatry 19:1115-1124.
- Merenlender-Wagner, A., Malishkevich, A., Shemer, Z., Udawela, M., Gibbons, A., Scarr, E., Dean, B., Levine, J., Agam, G., and Gozes, I. 2013. Autophagy has a key role in the pathophysiology of schizophrenia. Mol Psychiatry.
- Esteves, A.R., Gozes, I., and Cardoso, S.M. 2014. The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson’s disease. Biochim Biophys Acta 1842:7-21.
- Gozes, I., Yeheskel, A., and Pasmanik-Chor, M. 2014. Activity-Dependent Neuroprotective Protein (ADNP): A Case Study for Highly Conserved Chordata-Specific Genes Shaping the Brain and Mutated in Cancer. J Alzheimers Dis.
- 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.
- 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.
- Gozes, I., Schirer, Y., Idan-Feldman, A., David, M., and Furman-Assaf, S. 2014. NAP Alpha-Aminoisobutyric Acid (IsoNAP). J Mol Neurosci 52:1-9.
Public sites: http://www.sciencedaily.com/releases/2014/09/140909113625.htm
Illana Gozes, Ph.D.
Professor of Clinical Biochemistry
The Lily and Avraham Gildor Chair for the Investigation of Growth Factors
Director, the Edersheim Levie-Gitter Institute for Functional Brain Imaging
Head, the Dr. Diana and Zelman Elton (Elbaum)
Laboratory for Molecular Neuroendocrinology
Deparment of Human Molecular Genetics and Biochemistry
Sagol School of Neuroscience and Adams Super Center for Brain Studies
Sackler Faculty of Medicine