Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis

Abstract

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. Alzheimer Disease (AD) is the most common form of dementia, mainly attributed to altered processing and deposition of extracellular Aβ plaques and intracellular neurofibrillary tangles in the brain 1. Current understanding of AD pathophysiology indicates impairment of several cellular processes such as lipid metabolism, mitochondrial function and autophagy, leading eventually to cellular stress and death. A multifactorial model for AD proposes a cellular phase in which Amyloid beta (Aβ) pathology drives Tau hyperphosphorylation inducing cellular damage 2. Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2) autosomal dominant mutations are causative of familial AD (FAD) 3. FAD is characterized by its severity and earlier disease onset, together with severe brain atrophy indicating increased neuronal death 4. Presenilins are the catalytic component of the γ-secretase complex, playing a role in Aβ generation. The pathological severity of FAD suggests a direct neurodegenerative role of PS1 mutations, whether by increased production of toxic Aβ or by other mechanisms 5. Nevertheless, PS1 has also been related to other cellular functions, such as protein trafficking, Wnt/β-catenin signaling, apoptosis and the disruption of calcium homeostasis 6-8. Accordingly, PS1 mutations have been associated to increased cellular stress or death responses such as endoplasmic reticulum (ER) stress 9 , oxidative stress 10,11 , autophagy 12 , and apoptosis 13. Abnormal calcium homeostasis and its pathological role (calcium overload) in AD have attracted attention during recent years. Calcium ...

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