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Study identifies previously unknown proteins in Huntington’s disease pathology.

Huntington’s disease is an inherited disorder that damages nerve cells and causes parts of the brain to deteriorate, leading to uncontrolled movements and cognitive problems. There is no way to stop the disease’s progression, though medications can treat some symptoms.   The disease is caused by an expansion of a CAG (cytosine-adenine-guanine) triplet repeat in either of an individual’s two copies of a gene called Huntingtin.  Huntington’s disease (HD) is one of nine neurologic diseases caused by CAG expansion mutations that encode proteins containing expanded polyGln tracts.

While there is substantial evidence that the mutant huntingtin (HTT) gene and other polyGln proteins are toxic and contribute to disease, the vulnerability of specific brain regions is not yet understood.  Now, a study from researchers at the University of Florida has shown that the gene that causes the fatal disorder makes an unexpected ‘cocktail’ of previously unknown proteins that accumulate in the brain.  The team state that the findings are significant because these newly identified proteins kill neurons and were shown to build-up in regions of the brain that are most affected by the disease. The opensource study is published in the journal Neuron.

Previous studies show that in HD, expansions of more than 40 CAG repeats are associated with juvenile onset and increased disease severity. While nearly all research into the molecular mechanisms of HD have focused on the downstream effects of the mutant HTT protein, HD-antisense transcripts and CAG microRNAs have also been reported as playing a role in the disease.The discovery of repeat associated non-ATG (RAN) translation in spinocerebellar ataxia type 8 raises the possibility that sense and antisense mutant proteins may be expressed from the HD CAG expansion mutation.  The current study shows that along with a protein already implicated in Huntington’s disease, four other proteins also contribute to the disease pathology.

The current study examined the brains of 12 deceased adult and juvenile patients with Huntington’s disease. Data findings show that novel proteins were abundant in areas of patients’ brains that showed cell death, neuronal loss and other signs of disease, including neuroinflammation.  The lab explain that the disease stems from a genetic mutation in the Huntingtin gene that produces too many copies of a DNA segment known as CAG, which gives rise to a longer Huntingtin protein with toxic effects. However, the group observed that this DNA repeat mutation can undergo repeat associated non-ATG (RAN) translation, producing four additional damaging repeat proteins that accumulate in the brain. Results show that these RAN proteins are made without a signal in the genetic code that was previously thought to be required for protein production.

Results show that each of the four RAN proteins contains long repeats of certain single protein building blocks; with these repeat proteins too long for cells to deal with, they build up as aggregated clusters that kill cells.  The lab state that finding these novel RAN proteins in degenerated areas of the brain that were negative for the previously known mutant Huntington protein was crucial to linking them to the disease.

In addition to finding that the RAN proteins accumulate in the striatum, a specific brain region predominantly affected in Huntington disease, researchers also found them in the frontal cortex, cerebellum and white matter regions of the brain. The group state that to their knowledge this was the first time the accumulated proteins related to Huntington’s disease were extensively found in white matter, an inner part of the brain containing cells that support neuronal function.  The researchers state that in the cerebellum, a part of the brain at the back of the skull that controls movement and motor coordination, the discovery of RAN proteins suggests that they may be responsible for some of the typical uncontrolled movements observed in Huntington disease patients.

The team surmise on the basis of their findings, there is a possibility that RAN proteins contribute to eight other similar neurodegenerative disorders, including spinobulbar muscular atrophy and several types of spinocerebellar ataxia, which are also caused by an abnormal increase in the number of CAG repeats.  For the future, the researchers state that  further research is needed to understand how these proteins are being made without normal cellular signals and if strategies to block their production can be developed. They go on to conclude that in addition to the possibility of new therapies, detecting these proteins may be useful for predicting the disease’s onset, its progression and treatment responses.

Source:  University of Florida Health


Increased RAN Protein Staining in Juvenile HD.  Schematic diagram summarizing features of adult-onset and juvenile HD pathology.  RAN Translation in Huntington Disease.  Ranum et al 2015.
Increased RAN Protein Staining in Juvenile HD. Schematic diagram summarizing features of adult-onset and juvenile HD pathology. RAN Translation in Huntington Disease. Ranum et al 2015.

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