A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation.
Increasing biochemical and genetic evidence indicates that the amyloid-beta (Abeta) peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) pathogenesis. We previously reported that RanBP9 promotes Abeta generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Delta1/N60 (residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9. In this study, we found that RanBP9-N60, a processed form of RanBP9 virtually identical to the RanBP9-Delta1/N60 mutant, was strongly increased in AD brains compared with controls. To evaluate the potential pathogenic consequences of this phenotype, we studied the differential biological properties of full-length RanBP9 vs. RanBP9-Delta1/N60 in HEK293T and Neuro-2A cells. The RanBP9-Delta1/N60 fragment, which lacks a nuclear localization signal, displayed enhanced cytoplasmic vs. nuclear localization and >3-fold enhanced stability than full-length RanBP9. Importantly, RanBP9-Delta1/N60, which contains the LisH dimerization domain, retained the capacity to form self-interacting multimeric complexes and increased Abeta generation by approximately 5-fold over vector controls, more potent than the approximately 3-fold increase seen by full-length RanBP9. Taken together, these data indicate that RanBP9-N60 may further drive the amyloid cascade in AD and that the proteolytic processing of RanBP9 may be an attractive therapeutic target.
Lakshmana
Madepalli K
MK
Department of Neurosciences, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
Chung
John Y
JY
Wickramarachchi
Supul
S
Tak
Eileen
E
Bianchi
Elisabetta
E
Koo
Edward H
EH
Kang
David E
DE
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D016022:Case-Control Studies; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D046912:Multiprotein Complexes; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D046912:Multiprotein Complexes; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010446:Peptide Fragments; C116005:Ran binding protein 9; D011994:Recombinant Proteins