Brain Protein Structure Dictates Brain Health And Pathology: The Good, The Bad, And The Ugly

Nerve cells have long processes that connect one cell to the other, orchestrating nerve-cell networks and allowing the brain to function. A major brain protein called Tau is involved in facilitating dynamics and structure within the nerve cells. In dementia and many neurodegenerative diseases, Tau undergoes structural changes (becomes overly phosphorylated) and precipitates inside cells in structures known as neurofibrillary tangles. Dr. Alzheimer originally discovered these structures when he analyzed the brain of his first Alzheimer’s disease patient.

Tau is a product of a single gene, but once transcribed into RNA and then translated into a protein, it can form a dynamic Tau (three binding sites to the cellular skeleton and transport system – in short, 3R) or a stable Tau with an additional binding site (4R). In Alzheimer’s disease, the neurofibrillary tangles present 3R and 4R Tau forms. In contrast, there are pure 4R Tau pathologies like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

In our recent paper cited below, we show differential phosphorylation of Tau 4R and Tau 3R, which affect interaction with the cellular skeleton, thus affecting brain plasticity.

We further introduce NAP (davunetide, CP201) a drug candidate that enhances nerve cell plasticity, as preferring the 3R Tau and fortifying cell skeleton and transport system dynamics, thus preferably protecting against 3R or mixed Tau pathologies. These results unravel the precise molecular interactions that explain why NAP (davunetide, CP201) was not efficacious in PSP patients (4R Tau pathology) but showed efficacy in elderly patients suffering from amnestic mild cognitive impairment (3R+4R Tau pathology). The results further suggest the protection of brain developmental processes involving 3R Tau.

NAP is an active small fragment of an activity-dependent neuroprotective protein (ADNP). Children suffering from the ADNP syndrome (mutation in the ADNP gene) are characterized by global developmental delays, intellectual disabilities, and autistic traits, which can now be explained in part by deregulated interaction with 3R Tau, offering hope for CP201 development for the ADNP children.

Coronis Neurosciences (Professor Gozes, Chief Scientific Officer) is developing CP201 for the ADNP syndrome (US FDA, orphan drug designation).

Proteins keeping the nerve cell alive: Microtubules constitute the brain cell scaffold and transportation system within the cell. EB – microtubule end-binding proteins enhance Tau-microtubules connection, which is further enhanced by NAP (davunetide, CP201). P – phosphate. NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies. Credit: Illana Gozes

These findings are described in the article entitled NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies, recently published in the journal PLOS One.

Citation:

  1. Ivashko-Pachima Y, Maor-Nof M, Gozes I. PLoS One. 2019 Mar 13;14(3):e0213666. doi: 10.1371/journal.pone.0213666. eCollection 2019.

About The Author

Illana Gozes

Professor Emerita Illana Gozes, BSc, Tel Aviv University, Direct PhD, Weizmann Institute of Science (Best PhD Student Landau Prize), Israel, postdoc. MIT (Weizmann Fellowship) and Salk Institute, USA, Senior Scientist/Associate Professor, Weizmann Institute, Fogarty-Scholar-in-Residence, NIH, USA, currently, Professor for Clinical Biochemistry at Tel Aviv University (mentoring numerous students). She published >300 papers in neuroscience (h-index 74, >22,000 citations). Prof. Gozes is the inventor of many patents including CP201 (NAP, davunetide), a clinical drug candidate targeted at the rare disease indication, the ADNP syndrome (founded Allon Therapeutics and currently Chief Scientific Officer at Coronis Neurosciences). Professor Gozes discovered ADNP, an essential protein for brain formation implicated in autism, schizophrenia, Alzheimer’s disease and cancer. CP201 is a snippet of ADNP, enhancing ADNP’s protective activity. Prof. Gozes won many awards of excellence (including Tel Aviv University’s Vice President Award, Olson Prize, Julodan Prize, Teva Prize, Neufeld Award, Hanse-Wissenschaftskolleg (HWK) fellowship, Humboldt Award, Landau Prize for Life Achievements, 2013). Importantly, she is the Champion of Hope – Science International -2016, Global Genes. She is also the Ex-President of the Israel Society for Neuroscience, served on the Governing Committee and the Board of Governors of Tel Aviv University, currently serving on the Council of the European Society for Neurochemistry, the Israeli Ministry of Education, Council of Higher Education and is the Editor-in-Chief of the Journal of Molecular Neuroscience (Springer-Nature Press).

Yanina Ivashko-Pachima

Yanina Ivashko-Pachima is a research scientist at Tel Aviv University.

During my graduate studies, I have gained solid knowledge and substantial practical experience in molecular biology and biochemistry, especially within the context of understanding neurodegenerative diseases at the molecular and cellular level. I revealed a cellular mechanism of action of activity-dependent neuroprotective protein (ADNP – vital for brain formation) and an eight-amino-acid peptide NAP (a smallest active ADNP fragment). Discovered an ADNP/NAP effect on the microtubules (MTs), which are the major components of the neuronal cytoskeleton. As such, MTs are determining axonal transport, neurite formation and are vital for neural regeneration. In particular, I revealed the involvement of key MT dynamics regulators – Tau and end-binding proteins (EBs), in ADNP/NAP activity, and discovered the direct effect of NAP on this critical protein crosstalk. My work proposed NAP as a drug candidate protecting against MT deficiency, which is, to the best of my knowledge, currently the only approach, protecting MTs by increasing MT dynamics, unlike others MT-stabilizing drugs. Since MT and Tau impairments underlie a verity of neurodegenerative conditions, my findings may pave the path for peptide drug treatment against devastating diseases.

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