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Huntington's Defects Manifest Far from Damaged Brain Tissue
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Huntington's Defects Manifest Far from Damaged Brain Tissue
Question Raised on How Some Cells Can Tolerate Proteasome InhibitionIn 1872, a young physician published a paper about a new disease that would capture the attention of the medical world. The bizarre symptoms he described--grotesque movements, dementia, and mood swings--had been observed in people for centuries, but many attributed them to Satan and other supernatural forces. In a few eloquent paragraphs, 22-year-old George Huntington managed to wrest the disease from the grip of superstition and describe it for what it is--a rare and devastating hereditary condition with no known cause or cure.
"Our approach to Huntington's and other neurodegenerative diseases is to ask, why are only some neurons affected? And can we learn from the opposite--why are neighboring cells healthy?" said Ole Isacson (left) with Hyemyung Seo and Kai-Christian Sonntag. (Photo by Graham Ramsay)
Much has been learned about Huntington's disease in the past 130 years. For example, researchers have discovered that it is the result of a mutation in a single gene, dubbed huntingtin, and that it takes its greatest toll on neurons located in a structure deep in the center of the brain, the striatum. Yet in many respects, Huntington's disease--which affects 30,000 Americans--remains a bedeviling condition. There is still no cure, and patients invariably die several years after diagnosis. Though researchers have uncovered a plethora of clues, they still do not agree about what exactly causes striatal neurons to die. Part of the problem is that so much seems to go wrong with them.
It now appears that the huntingtin mutation produces similar disturbances in other areas of the brain and in other parts of the body, yet the affected cells somehow cope. A trio of McLean researchers compared striatal neurons of people with Huntington's disease to cells from their cortex, cerebellum, substantia nigra, and even to skin cells and found that these cells exhibit a remarkably similar pattern of defects without undergoing cell death. The findings by Hyemyung Seo, Kai-Christian Sonntag, and Ole Isacson appear in the September Annals of Neurology.
Hidden Weakness
On the face of it, the discovery appears to deepen the mystery of Huntington's disease. If striatal neurons are not the only ones to be affected by the huntingtin mutation, why do they alone fare so poorly? Though the researchers do not yet have answers, they believe that simply asking the question may be a step toward a better understanding of the disease and could point the way to potential therapies.
| "You get big aggregates, filled mainly with huntingtin protein. So you could imagine things getting stuck in the proteasome, and that would have effects on many other cellular processes." |
Striatal neurons in disease patients have multiple weaknesses. They are low on energy due to a lack of mitochondrial enzymes. They are missing special function-enhancing trophins. Perhaps most obvious, the mutation causes the cells to fill up with dense jots of misshapen protein. Researchers have recently suspected that misfolded proteins may be clogging the cell's waste disposal system, the proteasome, as they are known to do in other neuron-wasting diseases such as Parkinson's and Alzheimer's. But no one had actually demonstrated that proteasome activity was affected in Huntington's patients.
Though the huntingtin mutation causes defects in many cells in the brain and body, it takes its greatest toll on the spiny neurons of the striatum (above). (Image courtesy of Ole Isacson)
To explore the gap, Seo and Sonntag, both HMS instructors in psychiatry, and Isacson collected frozen brain material that had been donated to the McLean's brain bank and other repositories by the families of patients with advanced and latent Huntington's disease. Using a variety of assays, they found that proteasome activity was indeed lower than normal in the striatum of both sets of patients. To see if this was a striatum-only phenomenon, Seo and her colleagues measured proteasome activity in other brain regions--the cortex, cerebellum, and substantia nigra. They even measured it in skin fibroblasts, cells lying well outside the brain's precincts. Proteasome activity was low in every cell type tested from Huntington's patients --even in patients with no obvious signs of disease.
Searching for a telltale difference, one that would explain why striatal neurons are ultimately vulnerable to the disease process, the team assayed other recently discovered Huntington defects such as depleted brain-derived neurotrophic factor (BDNF) and mitochondrial complex II enzyme. Striatal cells of advanced Huntington's patients exhibited somewhat lower levels of mitochondrial complex II enzyme, but otherwise striatal and nonstriatal cells exhibited similar patterns.
A Proteasome SOS
While scrutinizing the Huntington's cells, Seo and her colleagues did notice that striatal neurons displayed higher levels of ubiquitin, the protein tag that cells place on proteins they want to get rid of--as though the cells were sending a distress signal to their proteasomes. The researchers also found signs of increased proteasome subunit expression in some Huntington's cells, as though the proteasomes had actually tried to respond to the crisis.In an effort to further rouse the proteasome, Seo and her colleagues introduced proteasome activator subunits into Huntington's and normal striatal neurons, using a lentiviral vector, an approach that had not been tried before. While proteasome activity increased markedly in normal cells, it did not budge in the diseased ones.
It is still not clear why the proteasomes shut down in Huntington's disease. "There is clogging around the cell, that is for sure. You get big aggregates, filled mainly with huntingtin protein. So you could imagine things getting stuck in the proteasome, and that would have effects on many other cellular processes," said Isacson.
Nor is it clear if the proteasome work stoppage is the cell's biggest problem. Huntingtin protein performs a variety of functions, including the turning on and off of BDNF production. Striatal neurons do not produce their own BDNF, but receive it from the cortex. Huntington's cortical cells, which were found to produce low levels of BDNF, may not be able to deliver the needed trophin and, in this way, may contribute to the striatum's demise.
Isacson believes that more clues to the vulnerability of striatal neurons will be found by stepping back and looking at the nature of the striatum. To begin, it is a very active area metabolically. Not only that, it receives an unusually high level of excitatory, or glutamate-mediated, inputs, which are notoriously damaging to the cell. Normal striatal neurons are known to be especially sensitive to excess glutamate, and Huntington's cells might be even more vulnerable. "The striatum is all set up in such a way that it would be a perfect place for neurotoxicity caused by Huntington's to wreak havoc with the cell," said Isacson. "I think of all these things as risk factors."
--Misia Landau