Polyglutamine stretches in proteins underlie a whole family of neurodegenerative diseases – the so-called poly-Q diseases. Huntington's disease is the most common member of the group, but it also includes less frequent disorders like spinocerebellar ataxia.

Now, researchers have found that a protein with polyglutamine repeats, pqn-41, may underlie a novel form of programmed cell death.

Their studies, which were published in the Feb. 24, 2012, issue of Science, were conducted in an invertebrate, the roundworm C. elegans. That animal sports a grand total of 302 neurons and has no spinal cord at all, and so, senior author Shai Shaham told BioWorld Today, drawing conclusions about the mechanisms of human neurodegenerative diseases is "certainly a speculative leap."

Still, C. elegans is a standard model organism in developmental biology – partly because with a total of only about 1,000 cells, the developmental path of each individual cell is easy to trace.

And in mammals, "although there is not a homolog per se, there are a few proteins that have general structural similarities" to pqn-41; that is, they have polyglutamine-rich regions and are roughly the same size as the worm protein.

Currently, programmed cell death is pretty much synonymous with apoptosis, which results from the activation of caspases and the expression of a group of pro-apoptotic proteins.

But animals lacking key apoptotic proteins can survive into adulthood, despite the fact that programmed cell death is critical during normal development. And scientists had previously observed that some cells undergo programmed cell death during development without activating apoptosis programs, prompting Shaham, who is an associate professor of developmental genetics at Rockefeller University, and his team to search for genes that could underlie an alternate form of programmed cell death.

In C. elegans, there is a type of cell – the linker cell, which plays a role in the development of the animals' sex organs – that dies during development without activating classical apoptosis programs. Shaham and his team used RNA interference to identify genes whose knockdown would prevent the death of linker cells. They identified five such genes, one of which specifically affected cell death.

When pqn-41 was knocked down, about 20 percent of linker cells survived.

Shaham and his team also looked at the morphology, or structure, of cells that die through a pqn-41-dependent mechanism, since apoptosis is "a morphological description of how cells die."

They found that the two types of death had distinctive morphologies. Cells that die via apoptosis are characterized by condensed chromatin and a shrinking cytoplasm. Organelles such as mitochondria and ribosomes do not seem to change much during apoptosis.

In contrast, dying linker cells are characterized by an indented nuclear membrane and swelling organelles. In that form of death, it is the chromatin that remains unchanged.

Those differences in how the dying cells look under the microscope are due to different underlying molecular machineries.

Shaham and his team plan to work out the molecular mechanisms of the new form of cell death in more detail. Earlier-than-normal expression of pqn-41 during development did not lead to massive cell death in C. elegans, which suggested that the protein needs one or more partners in crime to actually kill cells.

The scientists hope that finding such interaction partners may help them understand better why polyglutamine stretches in proteins are so damaging to the cell. Much like Abeta in Alzheimer's disease and alpha-synuclein in Parkinson's disease, mutant huntingtin protein, which contains a polyglutamine stretch, forms clumps in neurons in Huntington's disease. But "we don't really understand how you get from polyglutamine to cell death," either in normal development or poly-Q diseases, Shaham said.

Apoptosis is a process that has been targeted for the development of cancer drugs, and the new form of cell death, aside from its basic biological relevance, might offer similar possibilities if it can be induced in cancer cells. And Shaham said that he is "very interested in whether there is a connection" between the type of death he and his team have described, and cell death in Huntington's disease and other poly-Q diseases.

How widespread that type of cell death is in vertebrates remains to be seen. But it does appear to exist.

"Cells dying with similar morphology have been described during normal vertebrate development," he said, and that same morphology also has been observed "in some mouse models and human biopsies of polyglutamine diseases."

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