Abstract
Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events in the development of neurodegenerative processes, an idea called the “calcium hypothesis” of neurodegeneration. Caenorhabditis elegans (C. elegans) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (β-amyloid, α-synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca2+ dynamics studies in vivo at any time, by expressing Ca2+ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca2+ signaling in aging and neurodegeneration.
Highlights
Studying human diseases always requires the choice of the best possible model
The most frequent mutations are found in C9orf72 (10–15% of familial cases), the superoxide dismutase SOD1 enzyme (2%), the TDP-43 protein, which is a component of the ubiquitin-containing aggregates that appear in the motor neurons (0.9%), and the FUS protein (RNA-binding protein Fused in Sarcoma, 0.7%), mutations in many other genes have been found to be associated with this disease
These results suggest that the presenilin orthologue sel-12 has a critical role regulating endoplasmic reticulum (ER) to mitochondria Ca2+ transfer, and sel-12 mutations produce an increase of this Ca2+ transfer that plays a key role in the development of mitochondrial dysfunction, proteostasis, and neurodegeneration
Summary
Studying human diseases always requires the choice of the best possible model. humans would be the best subjects to study, but there are practical and ethical limitations that generally prevent them from being used as study subjects. The obvious choice is other mammals, mice, and they are excellent in many ways, when mimicking or studying behavioral phenotypes They have important limitations, both in how well they mimic some diseases, and in the slow development of pathologies and the time required to obtain conclusions. For those human genes having no orthologue in the worm, it is possible to generate “humanized” worms expressing the human gene, either wild-type or mutated, in defined tissues. Thanks to all these characteristics, C. elegans offers many advantages for studies of human diseases, and in particular, neurodegenerative diseases.
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