Huntington's disease protein helps wire the young brain

July 8, 2014
The protein associated with Huntington's disease, Htt, is critical in early brain development. Brains of five-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

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.

Huntington's disease is a progressive 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 .

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 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 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 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 .

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.

Explore further: Novel RNAi therapy silences mutated Huntington's disease gene and reduces symptoms

More information: "Huntingtin is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits," Spencer U. McKinstry, Yonca B. Karadeniz, Atesh K. Worthington, Wolodya Harapetyan, M. Ilcim Ozlu, Karol Serafin-Molina, W. Christopher Risher, Tuna Ustunkaya, Ioannis Dragatsis, Scott Zeitlin, Henry H. Yin, and Cagla Eroglu. Journal of Neuroscience, July 9, 2014. DOI: 10.1523/JNEUROSCI.4699-13.2014

Related Stories

Novel RNAi therapy silences mutated Huntington's disease gene and reduces symptoms

May 21, 2014
A targeted gene silencing strategy blocks production of the dysfunctional huntingtin (Htt) protein, the cause of Huntington's disease, a fatal, inherited neurodegenerative disorder. The effectiveness of this RNA interference ...

Study shows for first time how Huntington's disease protein could cause death of neurons

May 19, 2014
(Medical Xpress)—Scientists at the University of Pittsburgh School of Medicine have identified for the first time a key molecular mechanism by which the abnormal protein found in Huntington's disease can cause brain cell ...

New insight into the cellular defects in Huntington's disease

October 10, 2011
Huntington disease is a devastating neurogenerative disorder that causes a progressive loss of functional capacity and reduced life span. It is an inherited condition caused by a mutant HTT gene. Although this has been known ...

Fatal cellular malfunction identified in Huntington's disease

June 23, 2014
Researchers believe they have learned how mutations in the gene that causes Huntington's disease kill brain cells, a finding that could open new opportunities for treating the fatal disorder. Scientists first linked the gene ...

Immune cell migration is impeded in Huntington's disease

November 19, 2012
Huntington disease (HD) is an incurable neurodegenerative disease caused by a mutation in the huntingtin gene (htt). Though most of the symptoms of HD are neurological, the mutant HTT protein is expressed in non-neural cells ...

Huntington's disease: Hot on the trail of misfolded proteins' toxic modus operandi

February 19, 2014
Proteins are the workhorses of the cell, and their correctly folded three-dimensional structures are critical to cellular functions. Misfolded structures often fail to properly perform these vital jobs, leading to cellular ...

Recommended for you

Touching helps build the sexual brain

September 21, 2017
Hormones or sexual experience? Which of these is crucial for the onset of puberty? It seems that when rats are touched on their genitals, their brain changes and puberty accelerates. In a new study publishing September 21 ...

Gene immunotherapy protects against multiple sclerosis in mice

September 21, 2017
A potent and long-lasting gene immunotherapy approach prevents and reverses symptoms of multiple sclerosis in mice, according to a study published September 21st in the journal Molecular Therapy. Multiple sclerosis is an ...

Neuron types in brain are defined by gene activity shaping their communication patterns

September 21, 2017
In a major step forward in research, scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Cell a discovery about the molecular-genetic basis of neuronal cell types. Neurons are the basic building blocks that ...

Highly precise wiring in the cerebral cortex

September 21, 2017
Our brains house extremely complex neuronal circuits whose detailed structures are still largely unknown. This is especially true for the cerebral cortex of mammals, where, among other things, vision, thoughts or spatial ...

Your neurons register familiar faces, whether you notice them or not

September 21, 2017
When people see an image of a person they recognize—the famous tennis player Roger Federer or actress Halle Berry, for instance—particular cells light up in the brain. Now, researchers reporting in Current Biology on ...

Faulty cell signaling derails cerebral cortex development, could it lead to autism?

September 20, 2017
As the embryonic brain develops, an incredibly complex cascade of cellular events occur, starting with progenitors - the originating cells that generate neurons and spur proper cortex development. If this cascade malfunctions ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.