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Na, K-ATPase ?3 is a death target of Alzheimer patient amyloid-? assembly.

ABSTRACT: Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ?-protein (A?) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical A? oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase ?3 subunit (NAK?3). ASPD-binding to NAK?3 impaired NAK?3-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-A?-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAK?3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAK?3 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-NAK?3 interaction.

SUBMITTER: Ohnishi T

PROVIDER: S-EPMC4538662 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly.

Ohnishi Takayuki T Yanazawa Masako M Sasahara Tomoya T Kitamura Yasuki Y Hiroaki Hidekazu H Fukazawa Yugo Y Kii Isao I Nishiyama Takashi T Kakita Akiyoshi A Takeda Hiroyuki H Takeuchi Akihide A Arai Yoshie Y Ito Akane A Komura Hitomi H Hirao Hajime H Satomura Kaori K Inoue Masafumi M Muramatsu Shin-ichi S Matsui Ko K Tada Mari M Sato Michio M Saijo Eri E Shigemitsu Yoshiki Y Sakai Satoko S Umetsu Yoshitaka Y Goda Natsuko N Takino Naomi N Takahashi Hitoshi H Hagiwara Masatoshi M Sawasaki Tatsuya T Iwasaki Genji G Nakamura Yu Y Nabeshima Yo-ichi Y Teplow David B DB Hoshi Minako M

Proceedings of the National Academy of Sciences of the United States of America 20150729 32

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activate ...[more]

PMID: 26224839

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Project description:Na⁺/K⁺-ATPase maintains electrochemical gradients of Na⁺ and K⁺ essential for a variety of cellular functions including neuronal activity. The α-subunit of the Na⁺/K⁺-ATPase exists in four different isoforms (α1-α4) encoded by different genes. With a view to future use of pig as an animal model in studies of human diseases caused by Na⁺/K⁺-ATPase mutations, we have determined the porcine coding sequences of the α1-α3 genes, ATP1A1, ATP1A2, and ATP1A3, their chromosomal localization, and expression patterns. Our ATP1A1 sequence accords with the sequences from several species at five positions where the amino acid residue of the previously published porcine ATP1A1 sequence differs. These corrections include replacement of glutamine 841 with arginine. Analysis of the functional consequences of substitution of the arginine revealed its importance for Na⁺ binding, which can be explained by interaction of the arginine with the C-terminus, stabilizing one of the Na⁺ sites. Quantitative real-time PCR expression analyses of porcine ATP1A1, ATP1A2, and ATP1A3 mRNA showed that all three transcripts are expressed in the embryonic brain as early as 60 days of gestation. Expression of α3 is confined to neuronal tissue. Generally, the expression patterns of ATP1A1, ATP1A2, and ATP1A3 transcripts were found similar to their human counterparts, except for lack of α3 expression in porcine heart. These expression patterns were confirmed at the protein level. We also report the sequence of the porcine ATP1A3 promoter, which was found to be closely homologous to its human counterpart. The function and specificity of the porcine ATP1A3 promoter was analyzed in transgenic zebrafish, demonstrating that it is active and drives expression in embryonic brain and spinal cord. The results of the present study provide a sound basis for employing the ATP1A3 promoter in attempts to generate transgenic porcine models of neurological diseases caused by ATP1A3 mutations.

Dataset Information

Na, K-ATPase ?3 is a death target of Alzheimer patient amyloid-? assembly.

Publications

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly.

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