Monday, June 8, 2009

Study sheds light on Huntington disease with implications for other neurodegenerative disorders

A common theme among neurodegenerative diseases is that there is a some kind of "nucleating protein" which aggregates within specific areas of the brain. There is debate as to whether the aggregates cause disease, or are simply an attempt by brain cells to sequester bad proteins. If the former is true, then therapy should be aimed at disaggregating the bad protein. If the latter is true, then therapy should be focused on helping the brain to inactivate the free-floating bad proteins. A recent advance in the understanding of Huntington disease (HD) suggests that the free-floating form of the protein may be the culprit, lending support to the idea that other neurodegenerative diseases like Alzheimer's and Parkinson's may also be caused by soluble proteins rather than the aggregates that we neuropathologists focus on under the microscope.

Scientists have known for some time that HD is associated with a trinucleotide repeat mutation in the protein huntingtin on chromosome 4. But, since huntingtin is present throughout the brain, why does neurodegeneration in HD take place predominantly in the striatum (caudate and putamen)? Solomon H. Snyder and his team at Johns Hopkins University, in the June 5th issue of the journal Science, show that cytotoxicity in HD takes place because of the interaction of mutant huntingtin with a second protein, known as Rhes. It turns out that Rhes is a striatal specific protein, thus explaining the anatomic specificity of neurodegeneration in HD. Snyder and colleagues go on to show that cells in culture tend to sequester mutant huntingtin into an aggregate. But in the presence of Rhes, mutatant huntingtin cannot aggregate, suggesting that the soluble form of the bad protein is what causes damage.

An Associated Press article about the discovery posted on quotes Walter J. Koroshetz of NIH's National Institute of Neurological Disorders and Stroke as follows regarding the implications of this new study: "The answers in one disease may have implications for another... There's been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem."

The most famous Huntington patient was the iconic folk singer Woody Guthrie. And it was my colleague Doug W. Shevlin, who writes a pretty widely read music blog which today features a Woody Guthrie song, who alerted me to this break-through study. In a stroke of synchronicity, it so happens that my good friend Mark B. Weiss (pictured) is representing a performer at next month's Woody Guthrie Folk Festival in Okemah, Oklahoma.


Adam King said...

Interesting post Dr. M

Anonymous said...

I have not read the study in Science yet, so this may be premature. Dr Snyder's lab is deservedly highly respected, and the Rhes explanation for striatal specificity of HD makes a lot of sense. However if in the absence of Rhes abnormal huntingtin forms aggregates in neurons more readily, why are these inclusions more prevalent in other parts of the brain and absent in striatal cells? I think there are still pieces of this puzzle to be discovered and fit together.--Douglas C Miller MD,PhD