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New strategy discovered to combat Huntington’s disease

A strategy to selectively remove mutant proteins could combat neurodegeneration, according to new research, which showed this could be accomplished by using compounds that interact with the misfolded part of the protein and the neuron’s protein-clearance machinery.

Credit: Wikipedia Commons

Many neurodegenerative diseases involve the slow accumulation of a misfolded protein in neurons over many years, leading to the death of neurons from the build-up of toxic proteins. Scientists have long been searching for ways to reduce the levels of the disease-driving proteins without also clearing their wild-type counterpart.

Zhaoyang Li and a team of researchers focused on the Huntington’s disease, caused by an abnormally long stretch of glutamine amino-acid residues in the huntingtin (HTT) protein. This expanded polyglutamine tract causes HTT to misfold.

Affected individuals typically carry one copy of the HTT gene that encodes the mutant protein, and one allele that encodes a protein with the normal-length glutamine tract. Cells are able to degrade the mutant huntingtin (mHTT) through autophagy2 — a clearance mechanism that involves the engulfment of proteins.

The study hypothesized that compounds that bind to both the mutant polyglutamine tract and the protein LC3B, which resides in the autophagosome, would lead to engulfment and enhanced clearance of mHTT. But no such compounds had been reported.

So, Li and colleagues conducted small-molecule screens to identify candidate compounds and used wild-type HTT in a counter-screen to rule out compounds that bind to the normal version of the protein.

They initially identified two candidates, dubbed 10O5 and 8F20. These compounds had been shown to inhibit the activity of the cancer-associated protein c-Raf and kinesin spindle protein (KSP), which has a key role in the cell cycle. They found that 10O5 and 8F20 were able to clear mHTT independently of their effects on these other proteins.

The researchers showed that the regions of the two candidates that interacted with mHTT and LC3B in the screen shared structural similarities. Next, they screened for compounds that shared these structural properties but were structurally distinct from other c-Raf and KSP inhibitors. This led them to discover two more compounds, AN1 and AN2, that link mHTT to LC3B and thereby selectively reduce levels of mHTT.

The compounds leave levels of wild-type HTT unchanged. This is crucial because HTT has multiple neuronal functions, both during embryonic development and after birth. Existing mHTT-lowering strategies typically affect both HTT alleles, which is not ideal.

The authors found encouraging evidence that the compounds could produce functional improvements in models of Huntington’s disease across three species. Patient-derived neurons treated with each of the compounds showed significantly less shrinkage, degeneration of neuronal projections and cell death than was seen in untreated neurons.

At the same time, flies that model Huntington’s disease and were treated with the compounds recovered climbing ability and survived longer than did untreated counterparts. Also, treated mice that model Huntington’s disease showed improvements in three motor tests, compared with untreated mice.

Looking ahead, there are several research paths. First, establishing the mechanism by which Li and colleagues’ compounds recognize proteins with expanded polyglutamine tracts but spare normal proteins. Then, testing the compounds in other models of polyglutamine disorders and assessing their effects.

Brain tissue from a mouse shows star-shaped astrocytes (green). Cells (blue) containing mutant protein (white) display lower levels of a potassium-regulating protein (red). Photo: UCLA

Tweaking potassium in brain cells helps fight Huntington’s disease

Brain tissue from a mouse shows star-shaped astrocytes (green). Cells (blue) containing mutant protein (white) display lower levels of a potassium-regulating protein (red). Photo: UCLA

Brain tissue from a mouse shows star-shaped astrocytes (green). Cells (blue) containing mutant protein (white) display lower levels of a potassium-regulating protein (red). Photo: UCLA

Approximately one in 20,000 Americans suffer from Huntington’s disease, a devastating neurodegenerative affliction that  gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. Like other similar diseases, like Alzheimer’s, there isn’t any cure, but scientists at University of California, Los Angeles (UCLA) may have discovered a way to tackle it by looking elsewhere than other researchers. Namely, by boosting the potassium intake ability of a specific cell in the brain, the UCLA researchers improved walking and prolonged survival in a mouse model of Huntington’s disease.

Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene, namely a genetic defect on chromosome 4. The defect causes a part of DNA, called a CAG repeat, to occur many more times than it is supposed to. Normally, this section of DNA is repeated 10 to 28 times. But in persons with Huntington’s disease, it is repeated 36 to 120 times.  As the gene is passed down through families, the number of repeats tend to get larger. The larger the number of repeats, the greater your chance of developing symptoms at an earlier age. Therefore, as the disease is passed along in families, symptoms develop at younger and younger ages.

After onset, the disease gradually kills neurons causing the dreaded symptoms, while patients with aggressive cases can die in as little as 10 years. Most research has concentrated on neurons and their mechanics, looking on how these interact and how these genetic malfunctions cause Huntington’s. The UCLA researchers, however, took an alternate route and looked at what role astrocytes — large, star-shaped cells found in the brain and spinal cord — play in Huntington’s.

The stellar nebula in the brain

Artist impression of astrocytes. Photo: UCLA

Artist impression of astrocytes. Photo: UCLA

Astrocytes appear in almost equal number as neurons and enable the latter  to signal each other by maintaining an optimal chemical environment outside the cells. The scientists used two mouse models to explore whether astrocytes behave differently during Huntington’s disease: the first model studied an aggressive and early-onset type of Huntington’s; the second a slow-developing version.

In both models, astrocytes with the mutant gene showed a measurable drop in Kir4.1, a protein that allows the astrocyte to take in potassium through the cell membrane. This caused too much potassium to accumulate around the cell, disrupting the delicate chemical balance and causing neurons to grow oversensitive and fire too easily, disrupting nerve-cell function and ultimately the body’s ability to move properly. Ultimately this may be what causes the jerky motions common to Huntington’s disease.

To test if this hypothesis is correct, the researchers sought to find what would happen if they artificially increased Kir4.1 levels inside the astrocytes.  The results speak for themselves.

“Boosting Kir4.1 in the astrocytes improved the mice’s ability to walk properly,” said  Baljit Khakh, a UCLA professor of physiology and neurobiology. “We were surprised to see the length and width of the mouse’s stride return to more normal levels. This was an unexpected discovery.”
“Our work breaks new ground by showing that disrupting astrocyte function leads to the disruption of neuron function in a mouse model of Huntington’s disease,” said Michael Sofroniew, a UCLA professor of neurobiology. “Our findings suggest that therapeutic targets exist for the disorder beyond neurons.”
“We’re really excited that astrocytes can potentially be exploited for new drug treatments,” said Khakh. “Astrocyte dysfunction also may be involved in other neurological diseases beyond Huntington’s.”
Next, the researchers plan on exploring more of the astrocyte-neuron mechanisms in order to find out more how tweaking Kir4.1 levels alters neural networks. Findings appeared in Nature Neuroscience.