Calcium signaling in neurodegeneration

Abstract

Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival. Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer's disease, provides strong support for a role of calcium in neurodegeneration. These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.

Figure 1

Calcium signaling in synaptic plasticity. Synaptic activity results in the elevation of cytosolic calcium levels by promoting extracellular calcium influx (through opening of specific cell surface calcium channels, e.g. VGCCs or NMDAR) or ER calcium efflux (via activation of RyRs or InsP3Rs). Increased cytosolic calcium concentrations initiate the activation of several kinase-dependent signaling cascades leading to CREB activation and phosphorylation at Ser133, a process critical for protein synthesis-dependent synaptic plasticity and LTP.

Figure 2

Calcium homeostasis deregulations in neurodegenerative diseases. AD, PD, HD, and ALS affect cytosolic calcium levels by deregulating different homeostatic control mechanisms. NMDAR or AMPAR activities, calcium buffering proteins, and mitochondrial functions were found to be deregulated in the 4 neurodegenerative conditions. α-Synuclein and Aβ peptides, the building blocks of Lewy bodies in PD and of senile plaques in AD, respectively, can form calcium-permeable ion channels at the plasma membrane. Abnormal ER calcium efflux by a mechanism of oversensitization of InsP3R (in HD and FAD) and RyR (in FAD), or of inactivation of the ER pump SERCA (in FAD), was also observed.

Figure 3

The role of CALHM1 in calcium signaling: Relevance for APP metabolism and AD pathogenesis. CALHM1 is a cell surface protein of neuronal origin that shares sequence similarities with NMDAR. CALHM1 expression generates a calcium-selective cation current at the plasma membrane and controls cytosolic calcium concentrations, a mechanism that may lead to ERK1/2 activation (left panel). Importantly, the P86L mutation in CALHM1, which we found associated with an increased risk for AD in European populations, leads to an inhibition of the control of APP processing by CALHM1 (right panel). Consequently, the P86L mutation leads to a derepression of the effect of CALHM1 on Aβ accumulation and thus to an increase of Aβ levels. P86L-CALHM1 promotes Aβ accumulation via a loss of CALHM1 control on calcium permeability and cytosolic calcium levels [142]. Therefore, CALHM1 is a component of a novel cerebral calcium channel family involved in calcium signaling and Aβ metabolism, and thus may represent an important player in the calcium homeostasis deregulations observed in AD pathogenesis.