Genetic modifier for Huntington’s disease progression identified

A team led by UCL and Cardiff University researchers has developed a novel measure of disease progression for Huntington’s disease, which enabled them to identify a genetic modifier associated with how rapidly the disease progresses.

“We’ve identified a gene that could be a target for treating Huntington’s disease. While there’s currently no cure for the disease, we’re hopeful that our finding could be a step towards life-extending treatments,” said Dr Davina Hensman Moss (UCL Huntington’s Disease Centre, UCL Institute of Neurology), one of the lead authors of the Lancet Neurology study.

Huntington’s disease (HD) is a fatal neurological disease caused by a genetic mutation. Larger mutations are linked to rapidly progressing disease, but that does not account for all aspects of disease progression. Understanding factors which change the rate of disease progression can help direct drug development and therapies.

The research team used the high quality phenotypic data from the intensively studied TRACK-HD cohort of people with the HD gene mutation. They established that different symptoms of disease progress in parallel, so they were able to combine the data from 24 cognitive, motor and MRI brain imaging variables to generate their progression score for genetic analysis.

They then looked for areas of the genome associated with their progression measure, and found a significant result in their sample of 216 people, which they then validated in a larger sample of 1773 people from a separate cohort, the European Huntington’s Disease Network (EHDN) REGISTRY study.

The genetic signal is likely to be driven by the gene MSH3, a DNA repair gene which has been linked to changes in size of the HD mutation. The researchers identified that a variation in MSH3 encodes an amino acid change in the gene. MSH3 has previously been extensively implicated in the pathogenesis of HD in both mouse and cell studies. The group’s findings may also be relevant to other diseases caused by repeats in the DNA, including some spinocerebellar ataxias.

Dr Hensman Moss said: “The gene variant we pinpointed is a common variant that doesn’t cause problems in people without HD, so hopefully it could be targeted for HD treatments without causing other problems.”

Professor Lesley Jones (Cardiff University), who co-led the study, said: “The strength of our finding implies that the variant we identified has a very large effect on HD, or that the new progression measure we developed is a much better measure of the relevant aspects of the disease, or most likely, both.”

The researchers say their study demonstrates the value of getting high quality data about the people with a disease when doing genetic studies.

Professor Sarah Tabrizi (UCL Huntington’s Disease Centre), who co-led the study said: “This is an example of reverse translation: these novel findings we observed in people with HD support many years of basic laboratory work in cells and mice. Now we know that MSH3 is critical in the progression of HD in patients, we can focus our attention on it and how this finding may be harnessed to develop new therapies that slow disease progression.”

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Alzheimer’s, Parkinson’s, and Huntington’s diseases share common crucial feature

A Loyola University Chicago study has found that abnormal proteins found in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease all share a similar ability to cause damage when they invade brain cells.

The finding potentially could explain the mechanism by which Alzheimer’s, Parkinson’s, Huntington’s, and other neurodegenerative diseases spread within the brain and disrupt normal brain functions.

The finding also suggests that an effective treatment for one neurodegenerative disease might work for other neurodegenerative diseases as well.

The study by senior author Edward Campbell, PhD, first author William Flavin, PhD, and colleagues is published in the journal Acta Neuropathologica.

“A possible therapy would involve boosting a brain cell’s ability to degrade a clump of proteins and damaged vesicles,” Campbell said. “If we could do this in one disease, it’s a good bet the therapy would be effective in the other two diseases.”

Neurodegenerative diseases are caused by the death of neurons and other cells in the brain, with different diseases affecting different regions of the brain. Alzheimer’s destroys memory, while Parkinson’s and Huntington’s affect movement. All three diseases are progressive, debilitating and incurable.

Previous research has suggested that in all three diseases, proteins that are folded abnormally form clumps inside brain cells. These clumps spread from cell to cell, eventually leading to cell deaths. Different proteins are implicated in each disease: tau in Alzheimer’s, alpha-synuclein in Parkinson’s and huntingtin in Huntington’s disease.

The Loyola study focused on how these misfolded protein clumps invade a healthy brain cell. The authors observed that once proteins get inside the cell, they enter vesicles (small compartments that are encased in membranes). The proteins damage or rupture the vesicle membranes, allowing the proteins to then invade the cytoplasm and cause additional dysfunction. (The cytoplasm is the part of the cell that’s outside the nucleus).

The Loyola study also showed how a cell responds when protein clumps invade vesicles: The cell gathers the ruptured vesicles and protein clumps together so the vesicles and proteins can be destroyed. However, the proteins are resistant to degradation. “The cell’s attempt to degrade the proteins is somewhat like a stomach trying to digest a clump of nails,” Campbell said.

Flavin said the finding that protein clumps associated with the three diseases cause the same type of vesicle damage was unexpected. Loyola researchers initially focused on alpha-synuclein proteins associated with Parkinson’s disease. So they asked collaborator Ronald Melki, PhD, to send them samples of different types of alpha-synuclein. (To do the experiment in a blinded, unbiased manner, the Loyola researchers did not know which types of alpha-synuclein were which.) Melki, a protein researcher at the Paris-Saclay Institute of Neuroscience, is known for his ability to generate distinct types of alpha-synuclein. Without telling the Loyola researchers, Melki sent other types of proteins as well. This led to the surprise finding that tau and huntingtin proteins also can damage vesicles.

Campbell stressed the study’s findings need to be followed up and confirmed in future studies.

The Loyola study is titled, “Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.” It was supported by grants from the Michael J. Fox Foundation, Parkinson’s Disease Foundation, Illinois chapter of the ARCS Foundation, Arthur J. Schmitt Foundation and other sources.

Campbell is an associate professor in the Department of Microbiology and Immunology at Loyola University Chicago Stritch School of Medicine. Flavin is a Loyola University Chicago MD/PhD student. Other co-authors are Zachary Green, Stratos Skarpathiotis, and Michael Chaney of Loyola University Chicago; Luc Bousset and Ronald Melki of the Paris-Saclay Institute of Neuroscience; and Yaping Chu and Jeffrey Kordower of Rush University Medical Center.

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Basis of ‘leaky’ brain blood vessels in Huntington’s Disease identified

By using induced pluripotent stem cells to create endothelial cells that line blood vessels in the brain for the first time for a neurodegenerative disease, University of California, Irvine neurobiologists and colleagues have learned why Huntington’s disease patients have defects in the blood-brain barrier that contribute to the symptoms of this fatal disorder.

“Now we know there are internal problems with blood vessels in the brain,” said study leader Leslie Thompson, UCI professor of psychiatry & human behavior and neurobiology & behavior. “This discovery can be used for possible future treatments to seal the leaky blood vessels themselves and to evaluate drug delivery to patients with HD.”

The blood-brain barrier protects the brain from harmful molecules and proteins. It has been established that in Huntington’s and other neurodegenerative diseases there are defects in this barrier adding to HD symptoms. What was not known was whether these defects come from the cells that constitute the barrier or are secondary effects from other brain cells.

To answer that, Thompson and colleagues from UCI, Columbia University, the Massachusetts Institute of Technology and Cedars-Sinai Medical Center reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into brain microvascular endothelial cells — those that form the internal lining of blood vessels and prevent leakage of blood proteins and immune cells.

The researchers discovered that blood vessels in the brains of HD patients become abnormal due to the presence of the mutated Huntingtin protein, the hallmark molecule linked to the disease. As a result, these blood vessels have a diminished capacity to form new blood vessels and are leaky compared to those derived from control patients.

The chronic production of the mutant Huntingtin protein in the blood vessel cells causes other genes within the cells to be abnormally expressed, which in turn disrupts their normal functions, such as creating new vessels, maintaining an appropriate barrier to outside molecules, and eliminating harmful substances that may enter the brain.

In addition, by conducting in-depth analyses of the altered gene expression patterns in these cells, the study team identified a key signaling pathway known as the Wnt that helps explain why these defects occur. In the healthy brain, this pathway plays an important role in forming and preserving the blood-brain barrier. The researchers showed that most of the defects in HD patients’ blood vessels can be prevented when the vessels are exposed to a compound (XAV939) that inhibits the activity of the Wnt pathway.

This is the first induced pluripotent stem cell-based model of the blood-brain barrier for a neurodegenerative disease. The study appears in the journal Cell Reports, with a parallel study from Cedars-Sinai Medical Center in Cell Stem Cell that advances the first model for a neurodevelopmental disease that specifically affects the blood-brain barrier.

“These studies together demonstrate the incredible power of iPSCs to help us more fully understand human disease and identify the underlying causes of cellular processes that are altered,” said Ryan Lim, a postgraduate research scientist at the Institute for Memory Impairments and Neurological Disorders, or UCI MIND, who initiated the UCI work.

“We show a proof-of-concept therapy where we could reverse some of the abnormalities in the blood vessel cells by treating them with a drug,” added Thompson, who is affiliated with both UCI MIND and the Sue & Bill Gross Stem Cell Research Center.

“The future direction of this study is to develop ways to test how drugs may be delivered to the brain of HD patients and to examine additional treatment strategies using our understanding of the underlying causes of abnormalities in brain blood vessels,” said study co-leader Dritan Agalliu, assistant professor of pathology & cell biology at Columbia University Medical Center.

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Researchers identify link between birth defect, neurodegenerative diseases

A new study has found a link between neurological birth defects in infants commonly found in pregnant women with diabetes and several neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases. This is the first time this link has been identified; it may indicate a new way to understand, and perhaps treat, both neural tube defects and these neurodegenerative diseases.

The findings will be published in the Proceedings of the National Academy of Sciences.

“These results were really surprising,” said the study’s lead author, Zhiyong Zhao, PhD, a researcher at the University of Maryland School of Medicine (UM SOM). “The association suggests that these disparate diseases may have more in common than we previously realized.” The researchers on the article also include UM SOM Dean E. Albert Reece.

Neural tube defects occur when misfolded proteins accumulate in the cells of the developing nervous system. The misfolded proteins form insoluble clumps and cause widespread cell death, eventually leading to birth defects. Protein clumps also play a major role in Alzheimer’s, Parkinson’s and Huntington’s disease. In Alzheimer’s, for instance, this leads to the accumulation of plaques in the brain, reducing the ability of that organ to function.

The researchers studied pregnant mice with diabetes, and found that their embryos contained clumps of at least three misfolded proteins that are also associated with the three neurodegenerative diseases: ?-Synuclein, Parkin, and Huntingtin. It is not clear exactly how these protein clumps contribute to those diseases, but the link is well established.

This latest research also underscores the links between diabetes and some neurodegenerative diseases. People with diabetes have a higher risk of Alzheimer’s and Parkinson’s disease, and some research suggests that there are molecular links between Huntington’s and diabetes as well.

The scientists also examined whether it is possible to reduce levels of the misfolded proteins, and in so doing reduce neural tube defects. They gave diabetic pregnant animals sodium 4-phenylbutyrate (PBA), a compound that can reduce mistakes in molecular structure by aiding the molecules that ensure proper protein folding. In the animals that received PBA, there was significantly less protein misfolding, and fewer neural tube defects in the embryos. PBA has already been approved by the US Food and Drug Administration for other uses, and if it proves safe and effective in humans for this purpose, it could potentially reach patients much more quickly than an entirely new drug.

Neural tube defects are birth defects of the brain and spinal cord. They occur in the first month of pregnancy. The two most common are spina bifida and anencephaly. In the first, the fetal spinal column doesn’t close completely. This usually causes nerve damage, with some paralysis of the legs. In the latter, most of the brain and skull do not develop. Infants with this defect are usually stillborn or die soon after birth. Neural tube defects have several causes, including diabetes, folic acid deficiency, obesity in the mother, and consumption of certain medications. About 10 percent of women with diabetes who are pregnant will have embryos with neural tube defects.

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Cellular quality control process could be Huntington’s disease drug target

The loss of motor function and mental acuity associated with Huntington’s disease might be treatable by restoring a cellular quality control process, which Duke Health researchers have identified as a key factor in the degenerative illness.

Huntington’s disease is an inherited condition that results in the gradual erosion of nerve cells, leading to impairments and death. It affects about one in 10,000 people in the United States and has no cure.

Like other neuro-degenerative diseases such as Alzheimer’s and Parkinson’s, Huntington’s disease is caused when certain protein molecules fail to fold into the proper structural shape required for them to function properly. These misfolded proteins build up and become toxic to the nerve cells that control movement and thought.

In a study published online Feb. 13 in the journal Nature Communications, Duke Health researchers looked at what causes the failure of the cellular process that usually fixes or discards these misfolded proteins.

“Normally when proteins misfold, the cells have a mechanism to cope,” said senior author Dennis Thiele, Ph.D., George Barth Geller Professor in the Department of Pharmacology and Cancer Biology. “These quality control mechanisms can prod the proteins back into their normal three-dimensional shape, or if the damage is too extensive, target them for removal in the cellular garbage disposal. In Huntington’s disease, that’s not happening.”

Thiele and colleagues conducted experiments using yeast genetics, biochemistry, chemical biology screening, mouse models and stem cells from patients with Huntington’s disease. They found a biochemical explanation for how the quality control process breaks down in Huntington’s disease.

They focused on specialized proteins called chaperones — helpmates that coax the misfolded proteins into their correct conformations. Chaperone proteins are abnormally scarce in people with Huntington’s disease, but the cause of that scarcity was not known until now.

The Duke-led team found that the master control for chaperone production, called HSF1, was being destroyed in Huntington’s disease due to the presence of abnormally high levels of a chemical modifier called CK2. As a result, neurons die due to their inability to produce sufficient levels of the beneficial chaperones.

“We demonstrated that we could restore the abundance of the protein chaperones by chemically inhibiting CK2 in a cell model of Huntington’s disease, or genetically lowering CK2 kinase levels in a Huntington’s disease mouse model,” Thiele said. “In both cases, we dramatically increased the number of healthy neurons and we prevented the muscle wasting that is commonly observed in Huntington’s disease.”

With more functioning neurons, he said, the hallmarks of Huntington’s disease diminish. Thiele said there are potential investigational drugs that could delay or prevent the cellular processes that cause the neurodegeneration of Huntington’s disease, and could also be tested in Alzheimer’s and Parkinson’s, along with other similar diseases.

But he said more pre-clinical studies are needed to explore those chemicals and to further illuminate the cellular events involved.

“We have identified a potential new target for a drug intervention in Huntington’s disease,” Thiele said, “but there are a lot of basic questions that still need to be answered.”

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Huntington's disease linked to dysfunction of brain structure

Northwestern Medicine scientists identified a link between Huntington’s disease and dysfunction of the subthalamic nucleus, a component of the basal ganglia, a group of brain structures critical for movement and impulse control.

Huntington’s disease is characterized by the progressive loss of nerve cells in the brain and affects approximately 1 in 10,000 people. This fatal disorder is caused by a hereditary defect in a single gene.

“Although the genetic basis of the disease is well established, why the mutation leads to the expression of symptoms and loss of brain tissue remains poorly understood,” explained senior author Mark Bevan, professor of physiology at Northwestern University Feinberg School of Medicine.

The study was published Dec. 20 in the journal eLife.

The debilitating symptoms of Huntington’s disease typically manifest in adulthood and involve loss of motor and cognitive function, depression and personality changes. From the point of onset, symptoms develop and intensify over the following 10 to 25 years until death, typically due to complications associated with the disease.

“While research into Huntington’s disease has focused on other parts of the basal ganglia, the subthalamic nucleus has been largely overlooked,” said Bevan. “This is surprising because patients with Huntington’s disease have fewer nerve cells in the subthalamic nucleus. People who have suffered damage to the subthalamic nucleus exhibit excessive movement and impulsive behavior, similar to patients with Huntington’s disease.”

Using mice genetically engineered to carry the Huntington’s disease gene, scientists discovered the electrical activity of the subthalamic nucleus was lost. Furthermore, impaired subthalamic activity was caused by anomalous receptor signaling, leading to defective energy metabolism and accumulation of damaging oxidants. The authors also found abnormalities in the subthalamic nucleus occur earlier than in other brain regions, and that subthalamic nucleus nerve cells progressively degenerate as the mice age, mirroring the human pathology of Huntington’s disease.

“Our findings suggest early problems in the subthalamic nucleus not only contribute to the symptoms of Huntington’s disease, but are also likely to impair the processing capacity and health of other brain structures, more traditionally associated with the disease,” Bevan said.

Currently, there is no cure for Huntington’s disease; treatment can only alleviate some of the symptoms. A better understanding of aberrant brain receptor signaling that leads to nerve cell dysfunction could reveal a target for therapy, according to the authors.

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