The ADNP Derived Peptide, NAP Modulates the Tubulin Pool: Implication for Neurotrophic and Neuroprotective Activities
Open Access
- 14 December 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (12), e51458
- https://doi.org/10.1371/journal.pone.0051458
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.Keywords
This publication has 97 references indexed in Scilit:
- The role of Tau protein in resistance to paclitaxelCancer Chemotherapy and Pharmacology, 2011
- Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer's diseaseNeuroImage, 2011
- Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseasesHuman Molecular Genetics, 2010
- The β isotypes of tubulin in neuronal differentiationCytoskeleton, 2010
- Tubulin post-translational modifications: encoding functions on the neuronal microtubule cytoskeletonTrends in Neurosciences, 2010
- Tubulin polyglutamylation stimulates spastin-mediated microtubule severingThe Journal of cell biology, 2010
- Posttranslational Modifications of Tubulin and the Polarized Transport of Kinesin-1 in NeuronsMolecular Biology of the Cell, 2010
- Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon GuidanceCell, 2010
- Motor-dependent microtubule disassembly driven by tubulin tyrosinationThe Journal of cell biology, 2009
- Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signalingProceedings of the National Academy of Sciences of the United States of America, 2008