Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis
Standard
Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis. / Rojas-Charry, Liliana; Calero-Martinez, Sergio; Morganti, Claudia; Morciano, Giampaolo; Park, Kyungeun; Hagel, Christian; Marciniak, Stefan J; Glatzel, Markus; Pinton, Paolo; Sepulveda-Falla, Diego.
in: SCI REP-UK, Jahrgang 10, Nr. 1, 15.04.2020, S. 6455.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis
AU - Rojas-Charry, Liliana
AU - Calero-Martinez, Sergio
AU - Morganti, Claudia
AU - Morciano, Giampaolo
AU - Park, Kyungeun
AU - Hagel, Christian
AU - Marciniak, Stefan J
AU - Glatzel, Markus
AU - Pinton, Paolo
AU - Sepulveda-Falla, Diego
PY - 2020/4/15
Y1 - 2020/4/15
N2 - Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology.
AB - Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology.
U2 - 10.1038/s41598-020-63254-7
DO - 10.1038/s41598-020-63254-7
M3 - SCORING: Journal article
C2 - 32296078
VL - 10
SP - 6455
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -