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Aβ43‐producing PS 1 FAD mutants cause altered substrate interactions and respond to γ‐secretase modulation
Author(s) -
Trambauer Johannes,
Rodríguez Sarmiento Rosa María,
Fukumori Akio,
Feederle Regina,
Baumann Karlheinz,
Steiner Harald
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201947996
Subject(s) - mutant , presenilin , mutation , chemistry , protein subunit , microbiology and biotechnology , function (biology) , amyloid precursor protein , substrate (aquarium) , biochemistry , biology , alzheimer's disease , gene , disease , medicine , ecology , pathology
Abnormal generation of neurotoxic amyloid‐β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 ( PS 1) subunit of γ‐secretase is the major cause of familial Alzheimer's disease ( FAD ). Deeper mechanistic insight on the generation of Aβ43 is still lacking, and it is unclear whether γ‐secretase modulators ( GSM s) can reduce the levels of this Aβ species. By comparing several types of Aβ43‐generating FAD mutants, we observe that very high levels of Aβ43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of Aβ, are found for all mutants and are independent of their particular effect on Aβ production. Furthermore, unlike previously described GSM s, the novel compound RO 7019009 can effectively lower Aβ43 production of all mutants. Finally, substrate‐binding competition experiments suggest that RO 7019009 acts mechanistically after initial C99 binding. We conclude that altered C99 interactions are a common feature of diverse types of PS 1 FAD mutants and that also patients with Aβ43‐generating FAD mutations could in principle be treated by GSM s.