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DIR Papers of the Month

By Jerry Phelps
June 2006

Night Shift Work Protective for Parkinson's Disease?

Research results published in the April 15 edition of the American Journal of Epidemiology suggest that working night shifts may reduce a person's risk of developing Parkinson's disease. The study was conducted by Honglei Chen in the Epidemiology Branch at NIEHS along with colleagues at Brigham and Women's Hospital, the Massachusetts General Hospital, and Harvard School of Public Health.

The study looked at whether nurses working rotating night shifts were at a higher risk for developing Parkinson's disease compared with nurses who never worked night shifts. During 12 years of monitoring, the researchers documented 181 cases of Parkinson's disease in the 84,794 nurses who participated in the study. Nurses with 15 years or more of night shift work had 50 percent lower risk of Parkinson's disease.

The researchers also found that sleep duration was associated with Parkinson's disease risk. Nurses who reported nine or more hours of sleep per day were 84 percent more likely to develop Parkinson's disease than nurses who slept six hours or less.

Chen said "Working night shifts may be protective against Parkinson's disease or perhaps intolerance for night shift work is an early marker of Parkinson's disease." The authors warn that the novelty of these findings indicate that other studies are necessary to confirm or refute their results.

Previous research on this cohort of nurses from the U.S. Nurses' Health Study reported that night shift work was a risk factor for breast cancer development. These researchers postulated that nighttime exposure to bright lights interrupted the body's mainly nocturnal production of melatonin, a hormone produced by the pineal gland, and that this disruption somehow increased the risk of breast cancer. The current work was undertaken to further investigate the health effects of shift work.

Citation: Honglei Chen, Eva Schernhammer, Michael A. Schwarzschild, and Alberto Ascherio. A prospective study of night shift work, sleep duration, and risk of Parkinson's disease. Am. J. Epidemiol. 2006 163: 726-730.

New "Modifier Gene" Found that Affects the Severity of Cystic Fibrosis

Three researchers in the NIEHS Laboratory of Signal Transduction, Ling Yang, Jeff Reece and Stephen Shears, together with Sherif Gabriel at UNC, have discovered a "modifier gene" for cystic fibrosis (CF) known as inositol triphosphate kinase (ITPK1). The report appeared April 1 in the Journal of Cell Science.

CF is an inherited disease in which the composition of mucus changes dramatically. Although this disease affects several parts of the body, effects on the lungs provide the most serious clinical symptoms. Chronic obstruction of the airways is caused by an accumulation of thick sticky mucus in which pathogenic bacteria grow and thrive leading to progressive damage to the lungs.

CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Yet, what has puzzled researchers is that even in individuals with exactly the same mutation, a broad spectrum of disease severity exists; some CF patients die early in childhood, whereas others live well as adults with only mild lung

disease. These differences have led to a search for so-called "modifier genes" that might encode proteins that may either intensify or reduce the effects of the disease.

Shears and colleagues found that the main physiological function of ITPK1 is to synthesize an intracellular signaling molecule known as inositol (3,4,5,6)-tetrakisphosphate [Ins(3,4,5,6)P4]. Using tracheal epithelial cells in culture, they demonstrated that Ins(3,4,5,6)P4 inhibits secretion of chloride ions from the cells. This chloride movement would normally help the lungs secrete fluid and restore a more normal consistency to the mucus.

Other results show that variability in the degree of expression of ITPK1 alters the cellular levels of Ins(3,4,5,6)P4 and hence the degree of chloride secretion. These findings show that ITPK1 is a modifier gene for the CF condition. The authors argue that an improved ability to predict disease severity from analysis of genuine modifier genes "could offer new targets for more effective CF therapy earlier in life, before lung disease is irretrievably established." Work is continuing in an effort to improve understanding of how ITPK1 expression and cellular activity are regulated.

Citation: Yang L, Reece J, Gabriel SE, and Shears SB. Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis. J Cell Sci 2006 119: 1320-1328.

Cyclosporin Neurotoxicity and Timothy Syndrome Related to Aberrant Phosphorylation of the CaV1.2 Calcium Channel Protein

Investigators in the Laboratories of Neurobiology and Signal Transduction at NIEHS reported in the March 7 Proceedings of the National Academy of Sciences that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase the activity of CaV1.2 calcium channels in the cell surface by stimulating their phosphorylation.

Enzymatically adding or removing phosphate on proteins is the most common form of molecular regulation, but only occurs at very specific recognition sequences in the protein. Cyclosporin selectively inhibits an enzyme that removes phosphate from proteins. Inhibiting this enzyme, calcineurin, in immune cells prevents their activation, so cyclosporin is used widely to prevent organ rejection following transplantation. When it must be used for long periods of time; however, cyclosporin often has neurotoxic side effects.

Timothy syndrome is a much rarer but more severe condition that involves disruption of several organ systems. Conditions may include congenital heart disease, webbing of fingers and toes, immune deficiency, intermittent hypoglycemia and cognitive abnormalities. Timothy syndrome is caused by mutations in the CaV1.2 calcium channel that is the primary link between electrical activity and heart muscle contraction, hormone release from endocrine glands, and learning in the brain.

Although calcium is required for all of these cellular processes, injecting too much calcium into cells rapidly kills them. Consequently calcium channels rarely open for more than a thousandth of a second at any one time. However, as Armstrong, Birnbaumer and their colleagues established, phosphorylation of the CaV1.2 calcium channel at one specific site on the protein dramatically increases the duration of each opening. Cyclosporin exaggerates this effect by preventing the phosphate from being removed by calcineurin. Similarly, the mutation responsible for Timothy syndrome adds a second recognition site for the enzyme that adds the phosphate, so the channel is again hyperphosphorylated, resulting in prolonged calcium entry.

With the collaboration of Tom Darden in the Laboratory of Structural Biology, the NIEHS investigators also identified a potential structural mechanism for these effects which is similar to the mechanism of CaV1.2 channel regulation by dihydropyridines, drugs used clinically to treat human heart disease. Thus, there is now the potential to develop new drugs that selectively prevent the prolonged openings produced by hyperphosphorylation. These drugs could be used to prevent the neurotoxicity associated with chronic cyclosporin treatment or with Timothy syndrome.

Citation: Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y, BirnbaumerL, Armstrong DL. Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3932-7.

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