huntingtin

Scientists Develop Therapeutic Protein, Protect Nerve Cells from Huntington’s Disease

A new scientific study reveals one way to stop proteins from triggering an energy failure inside nerve cells during Huntington’s disease. Huntington’s disease is an inherited genetic disorder caused by mutations in the gene that encodes huntingtin protein. Approximately 30,000 Americans have mutant huntingtin protein which can impair energy-producing parts of nerve cells called mitochondria. The mutant protein destroys nerve cells and slowly chips away at a person’s ability to walk, speak, and control their behavior. Xin Qi, PhD, assistant professor of physiology and biophysics at Case Western Reserve University School of Medicine has been looking for proteins that interact with mutant huntingtin to better understand the initial steps of Huntington’s disease progression.

“Because mitochondrial dysfunction has been proposed to play an important role in the pathogenesis of Huntington’s disease,” said Qi, “we investigated the binding proteins of mutant huntingtin on mitochondria.” His recent study published in Nature Communications characterized one protein, valosin-containing protein (VCP) that Qi’s research team found in high abundance inside nerve cell mitochondria. Qi and colleagues discovered that VCP is recruited to nerve cell mitochondria by mutant huntingtin protein.

The researchers showed that mice with mutant huntingtin had mitochondria full of VCP, as did nerve cells donated by people with Huntington’s disease. The VCP inside mitochondria only interacted with mutant, but not healthy huntingtin protein. According to Qi, “In Huntington’s disease, the VCP-mutant huntingtin binding is greatly increased. This abnormal binding causes more VCP accumulation on the mitochondria,” Nerve cells with VCP-mutant huntingtin interacting inside them became dysfunctional and self-destructed.

“We found that VCP is a key player in mitochondria-associated autophagy, a mitochondria self-eating process. Over-accumulation of VCP on mitochondria thus results in a great loss of mitochondria, which leads to neuronal cell death due to lack of energy supply.” explained Qi. The researchers worked to identify ways to prevent VCP from heading to nerve cell mitochondria and interacting with mutant huntingtin protein once inside.
The team identified the regions of VCP and mutant huntingtin that were interacting. They cleverly designed a small protein, or peptide, with the same regions to disrupt the VCP-mutant huntingtin protein interaction. In nerve cells exposed to their peptide, VCP and mutant huntingtin bound the peptide instead of each other. Nerve cells exposed to the novel peptide had healthier mitochondria than unexposed cells. In fact, the peptide prevented VCP from relocating to mitochondria at all, and prevented nerve cell death.

Qi wanted to determine if the peptide had more than subcellular effects, and if it could be used therapeutically to prevent Huntington’s disease symptoms. The researchers administered the peptide to mice with Huntington’s-like disease and assessed mouse motor skills. Huntington’s-like mice exhibit spontaneous movement including excessive clasping, poor coordination, and decreased lifespan. Mice treated with the novel peptide did not experience these symptoms and appeared healthy. Qi concluded that the peptide reduced nerve cell impairment caused by Huntington’s disease in the animal model.

The study successfully countered harmful effects of mutant huntingtin and protected nerve cells in several models of Huntington’s disease. According to Qi, the interfering peptide developed in the study “suggests a potential therapeutic option for treatment of Huntington’s disease, a disease with no treatment available.” The next step for the researchers will be to optimize the potentially therapeutic peptide for use in human studies.

Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington’s chorea.  The disease is caused by an autosomal dominant mutation in either of an individual’s two copies of a gene called Huntingtin, which means any child of an affected person typically has a 50% chance of inheriting the disease. Physical symptoms of Huntington’s disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age.

Huntington’s Disease Protein Helps Wire the Young Brain

The protein that is mutated in Huntington’s disease is critical for wiring the brain in early life, according to a new Duke University study.

(Image caption: The protein associated with Huntington’s disease, Htt, is critical in early brain development. Brains of 5-week-old mice whose Htt was deleted show signs of cellular stress – reactive astrocytes (green) and microglia (white and red) and faulty connections – in brain circuits that have already been linked to the disease. Credit: Spencer McKinstry)

Huntington’s disease is a progressive neurodegenerative disorder that causes a wide variety of symptoms, such as uncontrolled movements, inability to focus or remember, depression and aggression. By the time these symptoms appear, usually in middle age, the disease has already ravaged the brain.

The new findings, published July 9 in the Journal of Neuroscience, add to growing evidence that Huntington’s and other neurodegenerative disorders, such as Alzheimer’s disease, may take root during development, said lead author Cagla Eroglu, an assistant professor of cell biology in the Duke University Medical School, and member of the Duke Institute for Brain Sciences.

“The study is exciting because it means that, if we understand what these developmental errors are, we may be able to interfere with the first stage of the disease, before it shows itself,” Eroglu said.

Several years ago, Eroglu and her team were looking for molecular players involved in the formation of new connections, or synapses, in early brain development in mice when their studies unexpectedly hit on the huntingtin (Htt) protein, which is present throughout the body and which forms clumps in the brain cells of people with Huntington’s disease.

“(Htt) had been implicated in certain cellular functions and synaptic dysfunction in Huntington’s, but the possibility that Htt is playing a direct role in synapse formation was not explored,” Eroglu said.

To understand the protein’s role as synapses form, the scientists created mice in which Htt is deleted only in the cortex, a part of the brain that is implicated in the disease and that controls perception, memory and thought.

At three weeks of age (roughly similar to the first two years of human life), a time when a mouse begins to take in its surroundings through its eyes and ears, the synapses of the mutant mice formed more rapidly compared with those of healthy mice, the scientists found.

 But by five weeks, when some synapses typically strengthen while others weaken in a normal process called pruning, the synapses had completely deteriorated in the mutant mice. In collaboration with another Duke researcher, Henry Yin, an assistant professor in psychology & neuroscience, the team also investigated the changes in synaptic function in these mutant mice and found severe alterations of the synaptic physiology.

Not only did the researchers see faulty circuits in the mice missing cortical Htt, they also saw signs of cellular stress in the brain, in the exact spot within the cortex that projects to the striatum, another brain area targeted by Huntington’s disease in people. “There’s something about that particular circuit that is vulnerable to changes in Htt,” Eroglu said.

The researchers also examined what happens in early brain development in a mouse model of Huntington’s disease. Similar to people with the disease, these animals have one normal copy of the Htt gene, and one mutated copy, which produces a protein that is present in cells but in expanded form.

The researchers found the same pattern: the Huntington’s disease model animals have synapses that initially mature much faster than normal in the cortex and then die off.

The new results also suggest that missing Htt for a prolonged period may not only affect the development but also the maintenance of healthy synapses, Eroglu said.

That’s especially relevant to a current strategy for treating Huntington’s disease: dialing down Htt levels in the brain using gene therapy or small-molecule inhibitors. But it has been a challenge to target the mutated copy of the gene, not the normal copy. Interested in the implications of lowering overall Htt levels, the group plans to delete Htt in the mouse brain later in life and measure the number of its synapses.

Other mouse models of the disease are also likely to have these faulty circuits. “We think this is probably a common thing, but that’s something we’re working on: whether we can detect early signs of faulty connections, correct it before the disease starts, and make these mice better,” Eroglu said.