The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells
Grace Woodruff,
Jessica E. Young,
Fernando J. Martinez,
Floyd Buen,
Athurva Gore,
Jennifer Kinaga,
Zhe Li,
Shauna H. Yuan,
Kun Zhang,
Lawrence S.B. Goldstein
Affiliations
Grace Woodruff
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Jessica E. Young
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Fernando J. Martinez
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Floyd Buen
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Athurva Gore
Department of Bioengineering, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Jennifer Kinaga
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Zhe Li
Department of Bioengineering, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Shauna H. Yuan
Department of Neurosciences, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Kun Zhang
Department of Bioengineering, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Lawrence S.B. Goldstein
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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.
