Abstract
Calcium (Ca2+) homeostasis is essential for cell maintenance since this ion participates in many physiological processes. For example, the spatial and temporal organization of Ca2+ signaling in the central nervous system is fundamental for neurotransmission, where local changes in cytosolic Ca2+ concentration are needed to transmit information from neuron to neuron, between neurons and glia, and even regulating local blood flow according to the required activity. However, under pathological conditions, Ca2+ homeostasis is altered, with increased cytoplasmic Ca2+ concentrations leading to the activation of proteases, lipases, and nucleases. This review aimed to highlight the role of Ca2+ signaling in neurodegenerative disease-related apoptosis, where the regulation of intracellular Ca2+ homeostasis depends on coordinated interactions between the endoplasmic reticulum, mitochondria, and lysosomes, as well as specific transport mechanisms. In neurodegenerative diseases, alterations-increased oxidative stress, energy metabolism alterations, and protein aggregation have been identified. The aggregation of α-synuclein, β-amyloid peptide (Aβ), and huntingtin all adversely affect Ca2+ homeostasis. Due to the mounting evidence for the relevance of Ca2+ signaling in neuroprotection, we would focus on the expression and function of Ca2+ signaling-related proteins, in terms of the effects on autophagy regulation and the onset and progression of neurodegenerative diseases.
Highlights
As a key second messenger, Ca2+ activates several signaling molecules and participates in a variety of physiological and pathological processes
The study results presented up to this point clearly demonstrates channel diversity and emphasizes the importance Ca2+ signaling has on autophagy regulation, with evidence suggesting that cellular Ca2+ signals are involved at different stages of the autophagy process, and playing roles in the initiation of phagophore formation and elongation and autophagosome/endosome fusion with the lysosome
Based on the results from a variety of experimental models, it is clear that specific Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD)-related proteins can disrupt Ca2+ homeostasis; the exact role that Ca2+ plays in apoptosis and autophagy regulation, especially in neurodegenerative diseases, remains unknown
Summary
As a key second messenger, Ca2+ activates several signaling molecules and participates in a variety of physiological and pathological processes. Signaling pathways utilizing Ca2+ are present during all stages of life, from egg fertilization to death, and have been implicated in several pathologies and aging. Ca2+ plays a central role in muscle contraction, cell proliferation, differentiation, metabolism, and death, as well as autophagy and other processes. There are several circumstances where altered Ca2+ concentrations, in an acute or chronic manner, lead to catastrophic cellular consequences, demonstrating the role this key second messenger has in controlling cell fate. We discussed the role of Ca2+ signaling in neurodegenerative diseases, highlighting the interplay between the proteins altered in those pathological conditions and the subsequent alterations in Ca2+ regulation. A better understanding of these processes is directly relevant to the onset and progression of neuronal cell death
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