Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer's Disease and Wolfram Syndrome

Abstract

Calcium ions (Ca²⁺) operate as important messengers in the cell, indispensable for signaling the underlying numerous cellular processes in all of the cell types in the human body. In neurons, Ca²⁺ signaling is crucial for regulating synaptic transmission and for the processes of learning and memory formation. Hence, the dysregulation of intracellular Ca²⁺ homeostasis results in a broad range of disorders, including cancer and neurodegeneration. A major source for intracellular Ca²⁺ is the endoplasmic reticulum (ER), which has close contacts with other organelles, including mitochondria. In this review, we focus on the emerging role of Ca²⁺ signaling at the ER-mitochondrial interface in two different neurodegenerative diseases, namely Alzheimer's disease and Wolfram syndrome. Both of these diseases share some common hallmarks in the early stages, including alterations in the ER and mitochondrial Ca²⁺ handling, mitochondrial dysfunction and increased Reactive oxygen species (ROS) production. This indicates that similar mechanisms may underly these two disease pathologies and suggests that both research topics might benefit from complementary research.

Keywords: Alzheimer’s disease; Wolfram syndrome; calcium; mitochondria; mitochondria-associated ER membranes (MAMs); neurodegeneration.

Figure 1

(A) Schematic representation of the Ca²⁺-signaling toolkit. Ca²⁺ can enter the cell via store-operated, STIM-gated Orai channels, but also through voltage-gated Ca²⁺ channels (VOC), arachidonic acid-regulated Ca²⁺ channels (ARC), transient receptor potential channels (TRP) and ligand-gated ion channels (LGIC). The plasma membrane Ca²⁺ ATPase (PMCA) and the plasmalemmal Na⁺/Ca²⁺ exchanger (NCX) are responsible for Ca²⁺ extrusion into the extracellular space. Ca²⁺ is mainly stored in intracellular Ca²⁺ stores, such as the endoplasmic reticulum, where it is buffered by calreticulin (CRT) and calnexin (CNX). Mobilization of Ca²⁺ from the ER into the cytosol occurs via two main channels, namely the inositol 1,4,5-trisphosphate receptor (IP₃R) and the ryanodine receptor (RyR). Multiple ER-Ca²⁺ leak channels exist including presenilin (PSEN), Bak inhibitor-1 (BI-1), TRP melastin 8 (TRPM8) and Sec61 translocon. ER Ca²⁺ depletion is detected by luminal ER Ca²⁺ sensors STIM1/STIM2, which subsequently activate plasmalemmal Orai to cause a Ca²⁺ influx across the plasma membrane. (Re)filling of the ER is mediated by the sarco-endoplasmic reticulum ATPase (SERCA). In the mitochondria, Ca²⁺ uptake is mediated by the voltage-gated anion channel (VDAC) on the outer mitochondrial membrane and the mitochondrial calcium uniporter (MCU) complex on the inner mitochondrial membrane. The main mitochondrial Ca²⁺ efflux transporter is the Na⁺/Ca²⁺ exchanger (NCLX). Lysosomal Ca²⁺ release is mediated by transient receptor potential mucolipin (TRPML) and two-pore channel 2 (TPC2). This latter is regulated by nicotinic acid adenine dinucleotide phosphate (NAADP). Cytosolic Ca²⁺ is buffered by several Ca²⁺-binding proteins including calmodulin (CaM), calbindin D-28 (CB-D28K), calretinin (CR) and parvalbumin (PV); (B–D): Schematic overview of relevant examples of functional correlates of Ca²⁺ signaling in specific tissue/cell types. CICR, Ca²⁺-induced Ca²⁺ release; SR, sarcoplasmic reticulum; ER, endoplasmic reticulum; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; LTP, long term potentiation; TRPM5, transient receptor potential cation channel subfamily M member 5.

Figure 2

Schematic overview of changes in ER Ca²⁺ handling occurring in Alzheimer’s disease. Mutations in presenilin (PSEN) were shown to increase the expression of the RyR and to cause an enhancement of IP₃R-mediated Ca²⁺ release. Additionally, the RyR is responsible for some of the IP₃R-mediated Ca²⁺ release through CICR. PSENs were also reported to form ER Ca²⁺ leak channels, a function that is abolished by PSEN mutations and which causes ER Ca²⁺ overload. PSEN mutations also display an inhibitory effect on store-operated Ca²⁺ entry, which may be involved in the generation of toxic Aβ deposits. Finally, PSENs interact with SERCA which also impacts the Aβ formation.

Figure 3

Schematic overview of the feed forward interplay between Ca²⁺ signaling and Aβ. Mutations in presenilin (PSEN) cause dysregulations in Ca²⁺ homeostasis, which then causes altered processing of APP and the formation of Aβ. In turn, this further impacts Ca²⁺ homeostasis.

Figure 4

Representation of the mitochondrial changes reported in Alzheimer’s disease. Aβ has been shown to induce mitochondrial Ca²⁺ overload via different mechanisms. For instance, Aβ inhibits Ca²⁺ extrusion by blocking the Na⁺/Ca²⁺ exchanger (NCLX). On the other hand, Aβ promotes Ca²⁺ uptake via interaction with mitochondrial Ca²⁺ uniporter (MCU). Aβ deposits are also detected inside the mitochondria where they further contribute to dysregulated Ca²⁺ homeostasis. The uptake of Aβ in the mitochondria is reportedly regulated by translocase of the outer membrane (TOM) machinery. The mitochondrial Ca²⁺ overload causes increased production of ROS and further leads to mitochondrial dysfunction.

Figure 5

Overview of the role of two Wolfram syndrome proteins on ER Ca²⁺ handling. Wolframin (Wfs1) stimulates IP₃R-mediated Ca²⁺ release both directly and via Neuronal Ca²⁺ Sensor 1 (NCS1). On the other hand, Cisd2 also interacts with the IP₃R in a direct and indirect manner. Cisd2 modulates B-cell lymphoma 2 (Bcl-2), which is a known inhibitor of the IP₃R. Both Wfs1 and Cisd2 were shown to interact with sarco-endoplasmic reticulum ATPase (SERCA).

Figure 6

Schematic overview indicating potential therapeutic strategies to target both Alzheimer’s disease and Wolfram syndrome. Possible therapeutic targets are indicated by a red asterisk. S1R, sigma 1 receptor; Bcl-2, B-cell lymphoma 2; IP₃R, inositol trisphosphate receptor; RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum ATPase; VDAC, voltage-dependent anion channel; Wfs1, wolframin.