Abstract:
:Presenilin 1 (PS1) is the catalytic core of γ-secretase, which cleaves type 1 transmembrane proteins, including the amyloid precursor protein (APP). PS1 also has γ-secretase-independent functions, and dominant PS1 missense mutations are the most common cause of familial Alzheimer's disease (FAD). Whether PS1 FAD mutations are gain- or loss-of-function remains controversial, primarily because most studies have relied on overexpression in mouse and/or nonneuronal systems. We used isogenic euploid human induced pluripotent stem cell lines to generate and study an allelic series of PS1 mutations, including heterozygous null mutations and homozygous and heterozygous FAD PS1 mutations. Rigorous analysis of this allelic series in differentiated, purified neurons allowed us to resolve this controversy and to conclude that FAD PS1 mutations, expressed at normal levels in the appropriate cell type, impair γ-secretase activity but do not disrupt γ-secretase-independent functions of PS1. Thus, FAD PS1 mutations do not act as simple loss of PS1 function but instead dominantly gain an activity toxic to some, but not all, PS1 functions.
journal_name
Cell Repjournal_title
Cell reportsauthors
Woodruff G,Young JE,Martinez FJ,Buen F,Gore A,Kinaga J,Li Z,Yuan SH,Zhang K,Goldstein LSdoi
10.1016/j.celrep.2013.10.018subject
Has Abstractpub_date
2013-11-27 00:00:00pages
974-85issue
4issn
2211-1247pii
S2211-1247(13)00602-5journal_volume
5pub_type
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