Caption: Left: High levels of the toxic ataxin-1 protein have destroyed nerve cells in the cerebellum of a mouse, causing a severe disease. Right: Here researchers have genetically blocked the genes that normally produce high levels of ataxin-1. This prevents the disease from developing and keeps the brain healthy.

Credit: Harry Orr, Department of Laboratory Medicine and Pathology, University of Minnesota

With our aging population, more people are developing neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. We currently don’t know how to prevent or cure these conditions, and their increasing prevalence not only represents a tragedy for affected individuals and their families, but also a looming public health and economic crisis.

Even though neurodegenerative diseases have varied roots—and affect distinct cell types in different brain regions—they do share something in common. In most of these disorders, we see some type of toxic protein accumulating in the brain. It’s as if the brain’s garbage disposal system is blocked, letting the waste pile up. In Huntington’s disease, huntingtin is the disease-causing protein. In spinocerebellar ataxia, it’s the ataxins. In Alzheimer’s, it’s beta-amyloid; in Parkinson’s, it’s α-synuclein. When garbage builds up in your kitchen, it’s a bad situation. When it’s in your brain, the consequences are deadly.

Last week, a team of NIH-funded researchers based at the Baylor College of Medicine in Texas and at the University of Minnesota revealed a clever way to identify genes that normally increase the levels of these rogue disease-causing proteins.

The team focused on spinocerebellar ataxia type 1 (SCA1)—an inherited, progressive, neurodegenerative disease that affects the cerebellum. SCA1 is caused by a mutation in the gene that produces ataxin-1. The mutation leads to a faulty ataxin-1 protein that resists removal. Rising levels of ataxin-1 kill neurons and destroy the cerebellum, and patients lose coordination, which affects walking, hand and eye movements, and speech.

Using fruit flies (yup, these insects are great for studying genetics), the researchers cranked up levels of ataxin-1 and proved that the more ataxin-1 that accumulates, the worse the neurodegeneration. This held true in both flies and mice. The researchers then used the fruit flies and human cells to screen for genes that reduce ataxin-1 and its toxicity. They discovered a network of proteins that regulate the levels of the ataxin-1 in brain cells—and importantly, these are proteins for which drugs have already been developed.

What is exciting is that lowering the level of ataxin-1 by decreasing these regulator proteins suppressed neurodegeneration in an SCA1 mouse model. If we can find drugs that can reduce ataxin-1 levels in human brain cells, there’s a chance we could treat or even prevent this devastating disease. Even more exciting, this same strategy might work for other neurodegenerative diseases. -Francis Collins

http://directorsblog.nih.gov/2013/06/04/protein-pile-up-common-cause-of-brain-disease/

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