Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?

Abstract

Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive in cold environments; it relies on molecular, cellular, and behavioral adaptations guided by the neuroendocrine system that together ensure unmatched tolerance to hypothermia, hypometabolism, and hypoxia. Therefore, hibernation is a useful model to study molecular neuroprotective adaptations to extreme conditions, and can reveal useful applications to human pathological conditions. In this review, we describe the known changes in Ca2+-signaling and the detection and activity of CBPs in the nervous system of vertebrate and invertebrate models during hibernation, focusing on cytosolic Ca2+ buffers and calmodulin. Then, we discuss these findings in the context of the neuroprotective and neural plasticity mechanisms in the central nervous system: in particular, those associated with cytoskeletal proteins. Finally, we compare the expression of CBPs in the hibernating nervous system with two different conditions of neurodegeneration, i.e., platinum-induced neurotoxicity and Alzheimer’s disease, to highlight the similarities and differences and demonstrate the potential of hibernation to shed light into part of the molecular mechanisms behind neurodegenerative diseases.

Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease

“…By contrast, a loss of Calb-ir neurons has been reported in the hippocampus (McLachlan et al, 1987;Stefanits et al, 2014), cerebral cortex (Ichimiya et al, 1988) and nucleus basalis of Meynert (Ichimiya et al, 1989;Riascos et al, 2011) in AD. In addition, there is an age-related decrease in PC Calb protein and mRNA levels in humans (Iacopino and Christakos, 1990;Gattoni and Bernocchi, 2019) and rodents (Iacopino and Christakos, 1990;Amenta et al, 1994;Kishimoto et al, 1998). The present findings revealed age as a cofactor underlying changes in Calb containing PCs.…”

“…PCs contain the calcium-binding proteins (CBPs) calbindin D-28k (Calb) and parvalbumin (Parv), while calretinin (Calr) is found exclusively in cells within the cerebellar granule cell layer (Bastianelli, 2003). CBPs maintain intracellular calcium homeostasis, which play a key role in synaptic function (Iacopino and Christakos, 1990;Airaksinen et al, 1997;Caillard et al, 2000;Bastianelli, 2003;Gattoni and Bernocchi, 2019). Disruption of cellular homeostasis, due to an increase of free cytoplasmic calcium, induces neuronal apoptosis (Orrenius et al, 2003).…”

MicroRNA dynamics during hibernation of the Australian central bearded dragon (Pogona vitticeps)

“…In the brain of hibernating bearded dragons tau protein kinases were upregulated 7 . Significant increases in MAPT phosphorylation has been observed in both mammalian and mollusc hibernation 4 , 53 – 55 . Increased phosphorylation of tau protein, such as by CAMKs, reduces its affinity for microtubules (reviewed in 56 ), destabilizing the microtubule, and potentially causing disruption of NMDAR anchoring.…”

New Approach for Untangling the Role of Uncommon Calcium-Binding Proteins in the Central Nervous System

“…In this case the binding of calcium and, therefore, the dispersion of local calcium does not cause major modification of the protein structure. They do not directly influence the activity of other macromolecules [ 21 ], instead, they moderate calcium transients. They modulate the shape and/or duration of Ca 2+ signals and help maintain Ca 2+ homeostasis.…”

“…The way in which calcium transients are affected is also influenced by the intracellular distribution and mobility of these calcium-buffers [ 22 ]. By modifying the calcium concentration, calcium buffers can indirectly affect neuronal excitability and synaptic plasticity [ 21 ].…”