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PMID:26224839

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Citation

Ohnishi, T, Yanazawa, M, Sasahara, T, Kitamura, Y, Hiroaki, H, Fukazawa, Y, Kii, I, Nishiyama, T, Kakita, A, Takeda, H, Takeuchi, A, Arai, Y, Ito, A, Komura, H, Hirao, H, Satomura, K, Inoue, M, Muramatsu, S, Matsui, K, Tada, M, Sato, M, Saijo, E, Shigemitsu, Y, Sakai, S, Umetsu, Y, Goda, N, Takino, N, Takahashi, H, Hagiwara, M, Sawasaki, T, Iwasaki, G, Nakamura, Y, Nabeshima, Y, Teplow, DB and Hoshi, M (2015) Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proc. Natl. Acad. Sci. U.S.A. 112:E4465-74

Abstract

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, 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-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 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-NAKα3 interaction.

Links

PubMed PMC4538662 Online version:10.1073/pnas.1421182112

Keywords

Alzheimer Disease/metabolism; Alzheimer Disease/pathology; Amino Acid Sequence; Amyloid beta-Peptides/toxicity; Animals; Calcium/metabolism; Cell Death/drug effects; Cells, Cultured; HEK293 Cells; Homeostasis/drug effects; Humans; Mass Spectrometry; Models, Biological; Models, Molecular; Molecular Imaging; Molecular Sequence Data; Molecular Weight; Neurons/drug effects; Neurons/metabolism; Neurons/pathology; Peptides/metabolism; Protein Aggregates; Protein Binding/drug effects; Rats; Signal Transduction/drug effects; Sodium/metabolism; Sodium-Potassium-Exchanging ATPase/chemistry; Sodium-Potassium-Exchanging ATPase/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PRIO

located_in

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

RAT:AT1A3

enables

GO:0001540: amyloid-beta binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002608)
  • happens_during:(UBERON:0000066)|occurs_in(CL:1001611)
  • happens_during:(UBERON:0000066)

Seeded From UniProt

complete

RAT:AT1A3

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002608)
  • existence_overlaps:(UBERON:0000066)|part_of(CL:1001611)
  • existence_overlaps:(UBERON:0000066)

Seeded From UniProt

complete

RAT:AT1A3

part_of

GO:0005890: sodium:potassium-exchanging ATPase complex

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

RAT:AT1A3

enables

GO:0005391: P-type sodium:potassium-exchanging transporter activity

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

RAT:AT1A3

involved_in

GO:1904646: cellular response to amyloid-beta

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002608)
  • happens_during:(UBERON:0000066)
  • occurs_in:(GO:0016020)
  • causally_upstream_of:(GO:1903407)

Seeded From UniProt

complete

RAT:AT1A3

enables

GO:0001540: amyloid-beta binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:736021

F

Seeded From UniProt

complete

HUMAN:AT1A3

enables

GO:0005391: P-type sodium:potassium-exchanging transporter activity

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AT1A3

located_in

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)

Seeded From UniProt

complete

HUMAN:AT1A3

located_in

GO:0030424: axon

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)|part_of:(UBERON:0013693)

Seeded From UniProt

complete

HUMAN:AT1A3

involved_in

GO:0060075: regulation of resting membrane potential

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

  • occurs_in:(CL:0000540)

Seeded From UniProt

complete

HUMAN:AT1A3

located_in

GO:0032809: neuronal cell body membrane

ECO:0000305: curator inference used in manual assertion

GO:0043025

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)

Seeded From UniProt

complete

HUMAN:AT1A3

involved_in

GO:1990535: neuron projection maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P05067

P

  • occurs_in:(CL:0002608)

Seeded From UniProt

complete

HUMAN:EPHB2

located_in

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ACHA7

located_in

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

RAT:CDK5

involved_in

GO:1904646: cellular response to amyloid-beta

ECO:0000314: direct assay evidence used in manual assertion

P

  • causally_upstream_of:(GO:0071902)
  • occurs_in:(CL:0002608)

Seeded From UniProt

complete

HUMAN:RAGE

located_in

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRIO

part_of

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:AT1A3

involved_in

GO:0060075: regulation of resting membrane potential

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

occurs_in:(CL:0000540)

Seeded From UniProt

complete

HUMAN:AT1A3

part_of

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)

Seeded From UniProt

complete

HUMAN:AT1A3

part_of

GO:0032809: neuronal cell body membrane

ECO:0000305: curator inference used in manual assertion

GO:0043025

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)

Seeded From UniProt

complete

HUMAN:AT1A3

part_of

GO:0030424: axon

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000598)
  • part_of:(UBERON:0001869)|part_of:(UBERON:0013693)

Seeded From UniProt

complete

HUMAN:AT1A3

involved_in

GO:1990535: neuron projection maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P05067

P

occurs_at:(CL:0002608)

Seeded From UniProt

complete

HUMAN:AT1A3

enables

GO:0001540: amyloid-beta binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002608)
  • happens_during:(UBERON:0000066)|occurs_in(CL:1001611)
  • happens_during:(UBERON:0000066)

Seeded From UniProt

complete

HUMAN:AT1A3

part_of

GO:0005890: sodium:potassium-exchanging ATPase complex

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

HUMAN:AT1A3

enables

GO:0005391: sodium:potassium-exchanging ATPase activity

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ACHA7

part_of

GO:0098794: postsynapse

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

RAT:GSK3B

involved_in

GO:1904646: cellular response to amyloid-beta

ECO:0000314: direct assay evidence used in manual assertion

P

  • causally_upstream_of:(GO:0071902)
  • occurs_in:(CL:0002608)

Seeded From UniProt

complete

Notes

See also

References

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