Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Na, K-ATPase a3 is a death target of Alzheimer patient amyloid-ß assembly.

Authors: Ohnishi, Takayuki  Yanazawa, Masako  Sasahara, Tomoya  Kitamura, Yasuki  Hiroaki, Hidekazu  Fukazawa, Yugo  Kii, Isao  Nishiyama, Takashi  Kakita, Akiyoshi  Takeda, Hiroyuki  Takeuchi, Akihide  Arai, Yoshie  Ito, Akane  Komura, Hitomi  Hirao, Hajime  Satomura, Kaori  Inoue, Masafumi  Muramatsu, Shin-ichi  Matsui, Ko  Tada, Mari  Sato, Michio  Saijo, Eri  Shigemitsu, Yoshiki  Sakai, Satoko  Umetsu, Yoshitaka  Goda, Natsuko  Takino, Naomi  Takahashi, Hitoshi  Hagiwara, Masatoshi  Sawasaki, Tatsuya  Iwasaki, Genji  Nakamura, Yu  Nabeshima, Yo-ichi  Teplow, David B  Hoshi, Minako 
Citation: Ohnishi T, etal., Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4465-74. doi: 10.1073/pnas.1421182112. Epub 2015 Jul 29.
Pubmed: (View Article at PubMed) PMID:26224839
DOI: Full-text: DOI:10.1073/pnas.1421182112

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ß-protein (Aß) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aß oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase a3 subunit (NAKa3). ASPD-binding to NAKa3 impaired NAKa3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aß-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKa3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKa3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKa3 interaction.

Annotation

Gene Ontology Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 11576284
Created: 2017-01-03
Species: All species
Last Modified: 2017-01-03
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.