Actin-microtubule crosslinker Pod-1 tunes PAR-1 signaling to control synaptic development and tau-mediated synaptic toxicity
| Autor: | Sunggyu Yoon, Song Her, Sangwoo Park, Kiyoung Kim, Mihye Lee, Yeongmi Cheon, Bingwei Lu, Seung-Il Oh, Ha-Young Kang, Jaekwang Kim, Seongsoo Lee, Hyungjun Kim |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aging Neuromuscular Junction Gene Expression tau Proteins Neuromuscular junction Article 03 medical and health sciences Glycogen Synthase Kinase 3 0302 clinical medicine Microtubule Cell polarity medicine Animals Drosophila Proteins Phosphorylation Actin Gene knockdown Amyloid beta-Peptides Chemistry Kinase General Neuroscience fungi Gene Expression Regulation Developmental Epistasis Genetic Cell biology 030104 developmental biology medicine.anatomical_structure Synapses Drosophila Neurology (clinical) Geriatrics and Gerontology Postsynaptic density 030217 neurology & neurosurgery Developmental Biology Signal Transduction |
| Zdroj: | Neurobiol Aging |
| ISSN: | 1558-1497 |
| Popis: | 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 Aβ 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 Aβ 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. |
| Databáze: | OpenAIRE |
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