Protective Cellular Process Discovered In ALS Disease

When Harvard School of Public Health (HSPH) scientists disabled a specific protein in mice that were genetically prone to develop ALS (Lou Gehrig’s disease), they expected — based on previous work — to hasten the onset of the paralyzing, lethal disorder.

What they found was the reverse. The paradoxical results not only shed light on the complex pathology underlying ALS (amyotrophic lateral sclerosis), but they also have given the researchers an idea for a new treatment strategy.

The team was lead by Claudio Hetz, Adjunct Assistant Professor of Immunology and Infectious Disease at HSPH, and Laurie Glimcher, Professor of Immunology at HSPH. They report in the September 17, 2009, online issue of Genes & Development that mice with the “knocked out” protein, a regulatory molecule called XBP1, fared better than their normally equipped counterparts. In females particularly, the motor nerves in the brain and spinal cord were markedly protected from the accumulation of abnormal, toxic proteins that progressively destroy neurons in ALS and in diseases like Alzheimer’s and Parkinson’s. As a result, the disease onset was delayed, and the mice lived an average of 10 days longer (although this was true only in females), even though they had been given a mutant gene known to cause some cases of ALS.

By turning off the XBP1 protein, the researchers had set in motion a process within the nerve cells that chewed up and got rid of the abnormal proteins created by the effects of the mutant ALS gene. Called autophagy — “self-eating” — it is a normal survival mechanism that probably evolved to cope with starvation; the cell cannibalizes its own less-important parts to nourish the components essential to life. Cells also use autophagy to digest and recycle their manufactured products, helping maintain a balance between synthesis and breakdown.

But for reasons the HSPH investigators need to further investigate, this protective autophagy in the ALS nerve cells was only unleashed when the XBP1 protein was shut down.

“XBP1 seems to be a repressor of autophagy in neurons, at least in ALS,” said Glimcher. And not only in rodents: The researchers said they observed the same phenomenon in spinal cord samples from patients affected with ALS.

In light of this discovery, she suggests, “One could conceive of selectively silencing XBP1 in neurons in the setting of ALS, perhaps through local delivery to the spinal cord.”

A hallmark of ALS and many other devastating neurological maladies is the failure of quality control within the nerve cells’ “endoplasmic reticulum,” or ER, where proteins are manufactured from building blocks. Newly made proteins can’t function correctly unless they are folded into a complex designated three-dimensional shape. In fact, incorrectly or “unfolded” proteins can be dangerous: They tend to form tough, insoluble fibers and accumulate in clumps that are toxic to the delicate neurons.

In ALS, it’s been found that a mutant causative gene, superoxide dismutase-1 (SOD1), can disrupt quality control in the endoplasmic reticulum, flooding the neurons with unfolded proteins. This situation is known as “ER stress.” When they sense this crisis, cells try to adapt through the Unfolded Protein Response (UPR) — an emergency drill aimed at increasing protein folding capacity. A key player in organizing this response is the XBP1 protein, a transcription factor that turns on and off other genes and proteins in the cell.

So when Glimcher, Hetz and their colleagues undertook experiments to further understand the role of the UPR in ALS, they first engineered mice with mutant SOD1 genes, setting the stage for ER stress and the production of unfolded proteins. In some of the mice, they also de-activated the XBP1 gene with the expectation of hampering the unfolded protein response, thus demonstrating that a failure of the UPR contributes to the onset of ALS.

When instead of hastening the neuron damage, the loss of XBP1 actually slowed the development of ALS pathology, the researchers realized that XBP1 must have a second function — namely, engaging autophagy within the cells, clearing them of toxic misfolded protein aggregates.

In their paper, the authors write that their research, “has uncovered a heretofore unappreciated crosstalk between autophagy and the Unfolded Protein Response in the nervous system.” Why the turning on of autophagy was dramatically more protective in the female rodents suggests that hormonal effects may be involved; thescientists point out that ALS is more common in males.

“Therapeutic strategies that reduce the level [of unfolded proteins] by increasing autophagy may be beneficial…in protein-folding disorders in the nervous system,” they conclude.

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