Key protein interactions involved in neurodegenerative disease revealed Read more at: http://medicalxpress.com/news/2012-11-key-protein-interactions-involved-neurodegenerative.html#jCp

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Medical Xpress

Medical research Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS)

.The study was published online ahead of print on November 8, 2012, by the journal Structure. The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration. "Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate coresponsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis. All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell's fate. "Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them." 

More information: "Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases," December 5, 2012 print edition of Structure. Journal reference: Structure Provided by Scripps Research Institute 

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Clinincal Advisor

Experts are not certain why this behavior occurs, but it may be related to late-day confusion, end-of-day exhaustion, and reduced lighting, which can increase shadows and possibly contribute to additional confusion. However, many times a reversed sleep-wake cycle is related to individuals napping during the day and not feeling sleepy at night.

Consider adding some structure and stimulation by encouraging more planned activities during the patient's day, such as taking a walk or attending a group daycare for older adults. Pay attention to the foods the patient is consuming, and encourage eating dinner early in the evening. Advise patients to avoid the use of caffeinated beverages, sweets, tobacco or alcohol, all which can cause hyperactivity when taken late in the day or early evening.

Increased activity at night may be attributable to an underlying condition, such as restless legs syndrome, bladder infection, incontinence and uncontrolled pain. Review all medications and be sure they are not contributing to the problem.

A mild sleep aid (e.g., trazodone [Desyrel, Oleptro] 25 mg) at night can help, but use with caution. For more information, visit the National Institute on Aging website.—Deborah L. Cross, MPH, CRNP, ANP-BC (153-06)