Source of Huntington's disease

Huntington's disease is a fatal hereditary disorder for which there is currently no treatment, it is associated with jerky movements and as these patients increasingly lose brain neurons, they slide into dementia. But the new research suggests that these symptoms may be a late manifestation of a disease that originates much earlier, in the first steps of embryonic development.

A team at Rockefeller led by Ali Brivanlou, the Robert and Harriet Heilbrunn Professor, developed a system to model Huntington's in human embryonic stem cells for the first time. Researchers describe early abnormalities in the way Huntington's neurons look, and how these cells form larger structures that had not previously been associated with the disease.

Huntington's is one of the few diseases with a straightforward genetic culprit: One hundred percent of people with a mutated form of the Huntingtin (HTT) gene develop the disease. The mutation takes the form of extra DNA, and causes the gene to produce a longer-than-normal protein. The DNA itself appears in the form of a repeating sequence, and the more repeats there are, the earlier the disease sets in.

Research on Huntington's has thus far relied heavily on animal models of the disease, and has left many key questions unanswered. For example, scientists have not been able to resolve what function the HTT gene serves normally, or how its mutation creates problems in the brain. Suspecting that the disease works differently in humans, whose brains are much bigger and more complex than those of lab animals, researchers developed a cell-based human system for their research. They used the gene editing technology CRISPR to engineer a series of human embryonic stem cell lines, which were identical apart from the number of DNA repeats that occurred at the ends of their HTT genes.

In cell lines with mutated HTT, we saw giant cells. It looked like a jungle of disorganization. When cells divide, they typically each retain one nuclei. However, some of these enlarged, mutated cells flaunted up to 12 nuclei-suggesting that neurogenesis, or the generation of new neurons, was affected. The disruption was directly proportional to how many repeats were present in the mutation: The more repeats there were, the more multinucleated neurons appeared.

There is an unrecognized developmental aspect to the pathology. Huntington's may not be just a neurodegenerative disease, but also a neurodevelopmental disease. Treatments for Huntington's have typically focused on blocking the activity of the mutant HTT protein, the assumption being that the altered form of the protein was more active than normal, and therefore toxic to neurons. However, Brivanlou's work shows that the brain disruption may actually be due to a lack of HTT protein activity.

To test its function, the researchers created cell lines that completely lacked the HTT protein. These cells turned out to be very similar to those with Huntington's pathology, corroborating the idea that a lack of the protein not an excess of it is driving the disease. The findings are significant because existing treatments that were designed to block HTT activity may actually do more harm than good.
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Eating at the same time regularly may fight dementia

 Regular meals improve gene expression in the region of the brain associated with body control, which often degenerates in Huntington's disease (HD); a form of dementia. Such eating habits also boost sleep quality and heart health, which are related to HD, in mice with the condition. Researchers believe the findings will also apply to humans and may improve the quality of life for patients with such incurable diseases.

Study author Professor Christopher Colwell, from The University of California, LA, said: 'HD is a genetically caused disease with no known cure.'  Lifestyle changes does not only improve the quality of life but also delay disease progression for HD patients are greatly needed. One group of mice were given food during a six-hour period when they were most active, which is at night as the animals are nocturnal.

The remainder ate whenever they liked. The quantity of food was the same between both groups. Professor Colwell said: 'In humans, the time of food availability would be during the day when food is normally consumed while the fast would be extended past the normal night. 'Feeding schedules play a role in the treatment of Huntington's disease'. Results reveal regular meal plans improve gene expression in the region of the brain associated with body control, known as the striatum, which often degenerates in HD.

Such eating habits also improve diseased mice's ability to run on a treadmill and balance on a beam, as well as assisting their heart rate, which is a sign of cardiovascular health. After three months of treatment, when mice reached the early disease stage, they showed improvements in their locomotor activity rhythm and sleep awakening time. The eating pattern  improved their heart rate variability, suggesting their nervous system dysfunction was improved.

Treated mice exhibited improved motor performance compared to untreated controls, this suggests feeding schedules could play a role in the treatment of HD and could lead to the development of new treatment options for neurodegenerative disorders. Regular meals boost gene expression in the brain region associated with body control. HD is a genetically caused disease with no known cure.

Lifestyle changes can improve the quality of life and delay disease progression for HD patients. Lifestyle interventions have been suggested to be preventative and therapeutic for diseases associated with ageing, such as type-2 diabetes, cardiovascular disease and neurodegenerative disorders.
Caloric restriction can prolong life span and protect against a variety of pathological conditions.
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