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Actin-microtubule crosslinker Pod-1 tunes PAR-1 signaling to control synaptic development and tau-mediated synaptic toxicity

Authors
Kang, Ha-YoungKim, Hyung-JunKim, KiyoungOh, Seung-IlYoon, SunggyuKim, JaekwangPark, SangwooCheon, YeongmiHer, SongLee, MihyeLu, BingweiLee, Seongsoo
Issue Date
Jun-2020
Publisher
ELSEVIER SCIENCE INC
Keywords
PAR-1; Pod-1; Synaptic defect; Tau-mediated synaptic toxicity; NMJ; Drosophila
Citation
NEUROBIOLOGY OF AGING, v.90, pp.93 - 98
Journal Title
NEUROBIOLOGY OF AGING
Volume
90
Start Page
93
End Page
98
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/610
DOI
10.1016/j.neurobiolaging.2020.02.005
ISSN
0197-4580
Abstract
Partitioning-defective 1 (PAR-1), a conserved cell polarity regulator, plays an important role in synaptic development, and its mutation affects the formation of synaptic boutons and localization of postsynaptic density protein Discs large (Dlg) at the neuromuscular junction (NMJ) in Drosophila. Drosophila PAR-1 and its human homolog, Microtubule affinity-regulating kinases (MARK), are also known to be implicated in Alzheimer's disease (AD) by controlling tau-mediated A beta toxicity. However, the molecular mechanisms of PAR-1 function remain incompletely understood. Here we identified Pod-1, an actin-microtubule crosslinker, which functionally and physically interacts with PAR-1 in Drosophila. Pod- 1 prominently co-localizes with PAR-1 in the postsynaptic region and regulates PAR-1 activity at the NMJ. Synaptic defects, including the reduction of boutons and delocalization of Dlg caused by PAR-1 overexpression, were rescued by Pod-1 knockdown. Conversely, the reduction of synaptic boutons in PAR-1 overexpressed NMJ was synergistically enhanced by the overexpression of Pod-1. Furthermore, Pod-1 increases the PAR-1 dependent S262 phosphorylation of tau, which is known to contribute to tau-mediated A beta toxicity. In line with the change of tau phosphorylation, Pod-1 knockdown rescued tau-mediated synaptic toxicity at the NMJ. Our results suggest that Pod-1 may act as a modulator of PAR-1 in synaptic development and tau-mediated toxicity. (C) 2020 Elsevier Inc. All rights reserved.
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