Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy.

The 1102-amino-acid activity-dependent neuroprotective protein (ADNP) was originally discovered by expression cloning through the immunological identification of its 8-amino-acid sequence NAPVSIPQ (NAP), constituting the smallest active neuroprotective fragment of the protein. ADNP expression is essential for brain formation and cognitive function and is dysregulated in a variety of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and schizophrenia). ADNP has been found to be mutated in autism, with an estimated prevalence of 0.17% (together, these autism cases now constitute ADNP syndrome cases) and our recent results showed somatic mutations in ADNP in Alzheimer's disease brains correlating with tauopathy. Furthermore, Adnp haploinsufficiency in mice causes an age-dependent reduction in cognitive functions coupled with tauopathy-like features such as an increased formation of tangle-like structures, defective axonal transport, and Tau hyperphosphorylation. ADNP and its derived peptides, NAP and SKIP, directly interact with end-binding proteins (EBs), which decorate plus-tips of the growing axonal cytoskeleton-microtubules (MTs). Functionally, NAP and SKIP are neuroprotective and stimulate axonal transport. Clinical trials have suggested the potential efficacy of NAP (davunetide, CP201) for improving cognitive performance/functional activities of daily living in amnestic mild cognitive impairment (aMCI) and schizophrenia patients, respectively. However, NAP was not found to be an effective treatment (though well-tolerated) for progressive supranuclear palsy (PSP) patients. Here we review the molecular mechanism of NAP activity on MTs and how NAP modulates the MT-Tau-EBs crosstalk. We offer a molecular explanation for the different protective potency of NAP in selected tauopathies (aMCI vs. PSP) expressing different ratios/pathologies of the alternatively spliced Tau mRNA and its resulting protein (aMCI expressing similar quantities of the dynamic Tau 3-MT binding isoform (Tau3R) and the Tau 4-MT binding isoform (Tau4R) and PSP enriched in Tau4R pathology). We reveal the direct effect of truncated ADNPs (resulting from de novo autism and newly discovered Alzheimer's disease-related somatic mutations) on MT dynamics. We show that the peptide SKIP affects MT dynamics and MT-Tau association. Since MT impairment is linked with neurodegenerative and neurodevelopmental conditions, the current study implicates a paucity/dysregulation of MT-interacting endogenous proteins, like ADNP, as a contributing mechanism and provides hope for NAP and SKIP as MT-modulating drug candidates. © 2021 Elsevier Inc. All rights reserved.

Citation

Yanina Ivashko-Pachima, Illana Gozes. Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy. Progress in molecular biology and translational science. 2021;177:65-90

PMID: 33453943

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