The ADNP Derived Peptide, NAP Modulates the Tubulin Pool: Implication for Neurotrophic and Neuroprotective Activities

Saar Oz,Yanina Ivashko-Pachima,Illana Gozes,Ashley I Bush

doi:10.1371/journal.pone.0051458

Saar Oz, Yanina Ivashko-Pachima + Show 2 more

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https://doi.org/10.1371/journal.pone.0051458

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Journal: PloS one	Publication Date: Dec 14, 2012
Citations: 162	License type: CC BY 4.0

Affiliation: Tel Aviv University

Abstract

Microtubules (MTs), key cytoskeletal elements in living cells, are critical for axonal transport, synaptic transmission, and maintenance of neuronal morphology. NAP (NAPVSIPQ) is a neuroprotective peptide derived from the essential activity-dependent neuroprotective protein (ADNP). In Alzheimer’s disease models, NAP protects against tauopathy and cognitive decline. Here, we show that NAP treatment significantly affected the alpha tubulin tyrosination cycle in the neuronal differentiation model, rat pheochromocytoma (PC12) and in rat cortical astrocytes. The effect on tubulin tyrosination/detyrosination was coupled to increased MT network area (measured in PC12 cells), which is directly related to neurite outgrowth. Tubulin beta3, a marker for neurite outgrowth/neuronal differentiation significantly increased after NAP treatment. In rat cortical neurons, NAP doubled the area of dynamic MT invasion (Tyr-tubulin) into the neuronal growth cone periphery. NAP was previously shown to protect against zinc-induced MT/neurite destruction and neuronal death, here, in PC12 cells, NAP treatment reversed zinc-decreased tau-tubulin-MT interaction and protected against death. NAP effects on the MT pool, coupled with increased tau engagement on compromised MTs imply an important role in neuronal plasticity, protecting against free tau accumulation leading to tauopathy. With tauopathy representing a major pathological hallmark in Alzheimer's disease and related disorders, the current findings provide a mechanistic basis for further development. NAP (davunetide) is in phase 2/3 clinical trial in progressive supranuclear palsy, a disease presenting MT deficiency and tau pathology.

Highlights

The key cytoskeletal elements, microtubules (MTs), are essential for axonal transport and synaptic transmission
The current set of experiments demonstrates that treatment with the activitydependent neuroprotective protein (ADNP) derived peptide NAP significantly affected the tubulin pool in rat neuronal, neuronal models (PC12) and glial cells in culture
In the neuronal differentiation model, the PC12 cell line, NAP-treatment significantly influenced a tubulin tyrosination cycle which is associated with MT dynamics in the living cell

Summary

Introduction

The key cytoskeletal elements, microtubules (MTs), are essential for axonal transport and synaptic transmission. MTs are major regulatory targets for axonal regeneration and their stability and organization determine axonal fate [1]. Tubulin isotype microheterogeneity is expressed at the level of the single neuron, with pronounced developmental changes in b-tubulin associated with neurites [2,3]. The isotype b3-tubulin is a neuronal marker in the developing and mature human nervous system [4,5]. B3tubulin plays a role in early neuritogenesis, concomitantly or in coordination with other MT associated proteins (MAPs) [6]. B3tubulin may promote neurite extension by enhancing MT polymerization during early neuritogenesis [7]. TTL is vital for neuronal organization and suppression of TTL in mice causes perinatal death [8]

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