New type of cell death may help neurons regenerate

A new type of cell death found in C elegans mimics cell death seen in human neurons, and may lead to regenerative therapies for human neuron injury.

C elegans (Caenorhabditis elegans), is a tiny (1 mm) worm studied by scientists as it is easy to grow, translucent, and its whole genome was sequenced in 2012. In C elegans, the linker cell is uniquely destined for termination only 2 days after forming. The linker cell exists only for 2 days, long enough to influence the shape of the male gonad and then die — just as the worm transitions from larvae to adult. This particular cell death is normal in the C elegans life cycle, although we don't understand the genetic and molecular mechanisms driving its function. All findings are reported in the journal eLife.

Shai Shaham PhD, head of The Rockefeller University's Laboratory of Developmental Genetics, had previously shown that the linker cell does not die by apoptosis, a commonly studied form of programmed cell death. Shaham adds: "Everything about this death process is different from apoptosis. It looks different under the microscope, it requires different genes, and it has different rates of biochemical reactions [kinetics]."

To figure out the molecular process behind linker, Shaham's team created mutations randomly in C elegans worms, and then searched for animals in which linker survived longer than 2 days. This identified mutations that only prolonged linker cell survival. One mutation in particular affected the protein HSF-1— known to shield cells from physiologic stresses, such as heat.

"It was a big surprise that HSF-1, which typically plays a protective role in the cell, was found to be such a key regulator of this newly observed type of cell death."

Shai Shaham PhD, head of The Rockefeller University's Laboratory of Developmental Genetics.

Shaham's lab found the HSF-1 protein performs two separate tasks in a cell, each totally independent from the other. When worms have normally functioning HSF-1 and their body temperature is raised (via lab experiments) to high temperatures, their linker cells survive longer than normal. Perhaps because HSF-1 protein is so busy protecting all cells from elevated heat stress, it fails to kill linker cells.

HSF-1 kills the linker cell by activating specific parts of a protein destruction apparatus called the ubiquitin proteasome system. Mutations in parts of this apparatus have been known to influence disintegration of the branchlike extensions of neurons that receive signals from other neurons. This mutation has been seen in Drosophila (fruit flies) as well as in mice, which suggests the ubiquitin proteasome pathway may exist across species — including C elegans.

Apoptosis is a form of programmed cell suicide that is well researched and understood. Scientists know which molecules induce it, suppress it, and what processes take place in the cell as it occurs. However, blocking apoptosis in mice has little effect on mouse development. Shaham: "This is a surprising observation, given how prevalent cell death is during growth. It suggests that other means of killing cells likely exist that we know little about."

The way linker cells are culled during worm development, resembles the way brain neurons are culled in mouse development. It is also similar to what happens in people with Huntington's disease and some other neurodegenerative disorders — and is also seen when nerve cells are severed in spinal injuries.

Based on these findings in C elegans, Shaham and his team hope to confirm whether or not the human version of these same proteins, might be involved in human neurodegeneration.

If this is the case, these proteins might also serve as targets for drugs to slow Huntington's disease — or help people regain mobility after a spinal injury.
 

"For example, if we stress nerve cells while they are dying, so that the HSF-1 protein is forced into a protective mode rather than a cell killing mode, perhaps we can slow nerve cell death," speculates Shaham.

Abstract
Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs are characterized, none appear to control developmental cell-culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in C. elegans and vertebrate development, and is therefore a compelling candidate-process complementing apoptosis. However, details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal-control pathway, and MAPKK signaling control HSF-1, a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin-proteasome-system, including the E2-ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, TAG-30/BTBD2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

Related Articles:
HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer; Cell Death and Disease (2014) 5, e980; doi:10.1038/cddis.2013.508
Published online 2 January 2014

Integrating the stress response: lessons for neurodegenerative diseases from C. elegans; Veena Prahlad, Richard I. Morimotoemail; Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA
DOI: http://dx.doi.org/10.1016/j.tcb.2008.11.002
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