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Protein Pile-up: Common Cause of Brain Disease

Posted on by Dr. Francis Collins

Two images, one dark, one bright, resembling a finger.

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.


RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Park J, Al-Ramahi I, Tan Q, Mollema N, Diaz-Garcia JR, Gallego-Flores T, Lu HC, Lagalwar S, Duvick L, Kang H, Lee Y, Jafar-Nejad P, Sayegh LS, Richman R, Liu X, Gao Y, Shaw CA, Arthur JS, Orr HT, Westbrook TF, Botas J, Zoghbi HY. Nature. 2013 May 29.

NIH support: National Institute of Neurological Disorders and Stroke


  • Chris Hempel says:

    Interesting article by Dr. Collins. In Niemann Pick Type C disease, the build-up causing the progressive neurodegeneration is from cholesterol.

    Many neurodegenerative diseases seem to be lysosomal storage diseases like NPC with different “garbage” building up inside the cells like what is described here.

    In Niemann Pick Type C, a non toxic compound called cyclodextrin (HPBCD) is removing the cholesterol or “garbage” from the cells and curing both NPC mice and cats that have Niemann Pick Type C. The compound is currently in human clinical trials, including with my twins.

    Cyclodextrin has also removed A-beta in Alzheimer’s mice and provided neuroprotection –

    It would be very interesting to test to see if cyclodextrin has any effect on the huntingtin disease-causing protein – as well as the ataxins. Interestingly, in Niemann Pick Type C, the Purkinje cells and the cerebellum are severely impacted like in SCA-1.

    I think cyclodextrin would also work in Creutzfeldt–Jakob disease (CJD), a human prion and neuro disease, that involves lipids/cholesterol.

    It’s worth some simple tests to see what proteins cyclodextrin might be able to solubalize since so many of these progressive neuro diseases seem to have similar mechanisms of action.

  • Eileen says:

    This is an exciting discovery and I’ll be looking forward and following new developments. I think that these brain diseases warrant more money for research. I’d rather see our money go to these brain debilatating and life destroying diseases rather than spending money for space travel etc.

  • p romano says:

    You make this sound like it is normally happening to everyone. Have you considered GMO foods as a cause?

  • LILLIAN KATZ says:

    Everything we eat, drink, hygene products, and especially all the unnecessary medications that doctors are prescribing are not healing, but causing brain disorders and serious harm leading to fatalities. CHECK ALL THE ADDITIVES, PRESERVATIVES, AND TOXIC CHEMICALS THAT HARM THE BRAIN’S CENTERAL NERVOUS SYSTEM.

  • Mawakana Motilewa says:

    I began incurring memory loss 3 years ago, and have read extensively to understand the neurodegeneration I am experiencing. Also, I learned of a few so-called solutions that would restore mental acuity. One such ‘solution’ suggested drinking black coffee, but I have drunk coffee most of my adulthood.

    Until now, I was unaware of the toxic protein build-up that Dr. Collins describes.
    I fully intend to discuss this article with my doctors, and to advocate for and support – financially and otherwise – continuing research in this area.

  • Janet Skidmore Cason says:

    I am always amazed at how Dr. Collins’ writing style makes science-based subjects easy to understand. It makes things especially fascinating.

    Thank you from someone who likes to learn.

  • Kim Paes says:

    Yes, very interesting indeed. I am involved in ocular disease research and drug developmen. The accumulation of disease causing proteins are also present in RPE cells and are thought to be the cause of diseases such as age-related macular degeneration, which leads to oxidative stress and RPE cell death.

  • Matthew Ricke says:

    cool pics.

  • Avery Blake says:

    I am 81, life time athlete (lacrosse Hall of Fame, still trying to stay involved), but have all the symtoms of early dementia. Taking Naranda and Donephy, and a couple of anti-cholesterol meds. If my case would be interesting to study, I’d do anything to help out.

  • Barbara S. says:

    This is interesting. I have Transverse Myelitis and I am in a study for serum Neurofilaments with my neurologists. I have memory problems and thought I might have Alzheimers disease since my Dad died of that, but that has been ruled out. I have also been told having TM which is the inflammation of the spinal cord, that this could also be causing the memory problems..

  • Gene A. says:

    I have a build up of Amyloid beta proteins in my brain. However Dr.s can’t diagnose anything because I have the double vision and associated imbalance issue with it also. Do you all know what it could be?

  • Suzanne says:

    It would be wonderful if we have a breakthrough in this as my Mum passed away with a neuro degenerative disease called Corticobasal Degeneration Syndrome….. it was a rare disease ….. I wouldn’t want anybody to suffer the way she did with this illness in the future if we can find some sort of cure for the future……

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