Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks

Abstract

Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β (Aβ) formation. Besides its enzymatic activity, PS2 is a multifunctional protein, being specifically involved, independently of γ-secretase activity, in the modulation of several cellular processes, such as Ca2+ signalling, mitochondrial function, inter-organelle communication, and autophagy. As for the former, evidence has accumulated that supports the involvement of PS2 at different levels, ranging from organelle Ca2+ handling to Ca2+ entry through plasma membrane channels. Thus FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability. In this contribution, we summarize the main findings on PS2, primarily as a modulator of Ca2+ homeostasis, with particular emphasis on the role of its mutations in the pathogenesis of FAD. Identification of cell pathways and molecules that are specifically targeted by PS2 mutants, as well as of common targets shared with PS1 mutants, will be fundamental to disentangle the complexity of memory loss and brain degeneration that occurs in Alzheimer’s disease (AD).

Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

“…In this Special Issue in Cells , six reviews address the newest results and advances in calcium signalling deregulation mechanisms in AD, how they are linked to other molecular players involved in AD pathogenesis, and the potential therapeutic approaches to correct calcium alterations to treat AD [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…Our review [ 23 ] and that by John McDaid et al [ 26 ] extensively highlight the role of PS1 in controlling several aspects of the subcellular calcium signalling deregulation and in synaptic plasticity. The review by Paola Pizzo et al [ 28 ] specifically focuses on the role of PS2 in the modulation of ER and Golgi apparatus calcium handling, calcium entry through the plasma membrane channels, mitochondrial function, ER–mitochondria communication, and autophagy. The authors overview the alterations of calcium homeostasis observed in several cell lines expressing FAD-PS2 mutants, in human-derived fibroblasts, and in PS2 mice and ex vivo models (primary neurons culture and acute hippocampal slices) [ 28 ].…”

“…The review by Paola Pizzo et al [ 28 ] specifically focuses on the role of PS2 in the modulation of ER and Golgi apparatus calcium handling, calcium entry through the plasma membrane channels, mitochondrial function, ER–mitochondria communication, and autophagy. The authors overview the alterations of calcium homeostasis observed in several cell lines expressing FAD-PS2 mutants, in human-derived fibroblasts, and in PS2 mice and ex vivo models (primary neurons culture and acute hippocampal slices) [ 28 ]. Of most interest, they discuss the impact of familial PS2 mutations in the control of multiple aspects of cell and tissue physiology, including cell metabolism and bioenergetic and brain network excitability [ 28 ].…”

“…The authors overview the alterations of calcium homeostasis observed in several cell lines expressing FAD-PS2 mutants, in human-derived fibroblasts, and in PS2 mice and ex vivo models (primary neurons culture and acute hippocampal slices) [ 28 ]. Of most interest, they discuss the impact of familial PS2 mutations in the control of multiple aspects of cell and tissue physiology, including cell metabolism and bioenergetic and brain network excitability [ 28 ].…”

Calcium Signaling and Mitochondrial Function in Presenilin 2 Knock-Out Mice: Looking for Any Loss-of-Function Phenotype Related to Alzheimer’s Disease

“…Cytosolic Ca 2+ Handling in PS2-/-Neurons Cytosolic Ca 2+ responses were evaluated in primary cortical neuronal cultures from WT and PS2-/-newborn mice. Since PS1 and PS2 can have differential effects on cell Ca 2+ handling (revised in [30]), and a coregulation of PS1 and PS2 expressions has been previously reported [5,31], we firstly assessed PS1 expression level in WT and PS2-/cortical neurons finding a slight increase, although nonsignificant, in this protein in the absence of PS2 (Figure S1A).…”