AUTHOR=Ivashko-Pachima Yanina , Gozes Illana 

TITLE=A Novel Microtubule-Tau Association Enhancer and Neuroprotective Drug Candidate: Ac-SKIP

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=13

YEAR=2019

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2019.00435

DOI=10.3389/fncel.2019.00435

ISSN=1662-5102

ABSTRACT=<p>Activity-dependent neuroprotective protein (ADNP) has been initially discovered through its eight amino acid sequence NAPV<underline>SIP</underline>Q, which shares SIP motif with SALLR<underline>SIP</underline>A – a peptide derived from activity-dependent neurotrophic factor (ADNF). Mechanistically, both NAPV<underline>SIP</underline>Q and SALLR<underline>SIP</underline>A contain a SIP motif that is identified as a variation of SxIP domain, providing direct interaction with microtubule end-binding proteins (EBs). The peptide SKIP was shown before to provide neuroprotection <italic>in vitro</italic> and protect against Adnp-related axonal transport deficits <italic>in vivo</italic>. Here we show, for the first time that SKIP enhanced microtubule dynamics, and prevented Tau-microtubule dissociation and microtubule disassembly induced by the Alzheimer’s related zinc intoxication. Furthermore, we introduced, CH<sub>3</sub>CO-SKIP-NH<sub>2</sub> (Ac-SKIP), providing efficacious neuroprotection. Since microtubule – Tau organization and dynamics is central in axonal microtubule cytoskeleton and transport, tightly related to aging processes and Alzheimer’s disease, our current study provides a compelling molecular explanation to the <italic>in vivo</italic> activity of SKIP, placing SKIP motif as a central focus for MT-based neuroprotection in tauopathies with axonal transport implications.</p>