The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells

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 non-neuronal systems. We used isogenic euploid human iPSC 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.

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

“…Drug development, and eventually drug treatment, may need to be individualized for specific APP mutations based on a better understanding of their individual downstream affects. The use of induced pluripotent stem cell (IPS)-derived neuronal patient lines and AD mutations introduced by genome editing in isogenic neuronal IPS lines (Israel et al, 2012;Kondo et al, 2013;Muratore et al, 2014;Shi et al, 2012;Woodruff et al, 2013;Yagi et al, 2011) could therefore act as a valuable new tool for future studies of these different ADs.…”

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models

“…The first study to do so in the context of AD was an allelic series of PSEN1. Woodruff et al knocked in the PSEN1ΔE9 mutation into a control background using TALEN-mediated genome editing (Woodruff et al, 2013). The PSEN1ΔE9 mutation causes a loss of exon 9 and the ability of PSEN1 protein to undergo endoproteolysis to its mature form (Perez-Tur et al, 1995).…”

Alzheimer's Disease

“…In one such study, PS1 mutation was found to affect the γ-secretase function but not other functions of PS1. Therefore, the mutational effect is a mixture of loss of and gain of functions (Woodruff et al, 2013). In another study, Aβ42/ Aβ40 ratio was found to be higher in the PS1 mutant NPC.…”