NEWS |
LIKELY CAUSES FOR PSORIASIS FOUND
STUDY LINKS FOUR PROTEINS TO TRIGGERING PSORIASIS
the world. Of the roughly 50,000 proteins in the human body, researchers have zeroed in on four that appear most likely to contribute to this chronic disease. The findings, published last month in Molecular & Cellular Proteomics, dramatically advance efforts to understand how psoriasis develops and, in turn, how to stop it.
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Causes and prevalence ‘Psoriasis affects 2 to 3% of the population worldwide,’ said senior author Nicole L. Ward, PhD, associate professor of dermatology and neurosciences, Case Western Reserve University School of Medicine. ‘The underlying cause of psoriasis remains unknown, and the specific signals that trigger disease onset are still being investigated. There currently is no cure.’ Ward’s lab is focused on studying the pathogenesis of the disease and its co-morbidities, including heart attack and stroke. Her group is actively working to identify new molecules key to the disease process that could become potential drug targets. Psoriasis is an autoimmune skin disease
characterised by well-demarcated areas of red, raised and scaly skin next to areas of normal-appearing skin. Another complication of psoriasis is joint involvement, a condition termed psoriatic arthritis.
Study design Ward and her team first narrowed their pool of potential culprits to about 1,280 proteins that are differentially regulated in the condition. From there, they focused on five that stood out either because of their high prevalence in human psoriasis or their prominence in other studies relating to human psoriasis tissue. Ward’s
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KLK6 protein
ase Western Reserve scientists have taken a huge leap toward identifying root causes of psoriasis, an inflammatory skin condition affecting 125 million people around
lab team took skin tissue samples from her well-established psoriasis transgenic mouse model, called the KC-Tie2 mouse, and compared it to skin tissue samples of normal mice. Her lab collaborated with Mark R. Chance, PhD, director of the Center for Proteomics and Bioinformatics, CWRU School of Medicine, and his team at the center to identify new proteins that were differentially regulated in the skin tissue of psoriasis mice compared to the skin tissue of healthy mice. To ensure that the proteins identified in the mouse were important to human psoriasis, her team then examined human psoriasis skin cells, known as keratinocytes, and human psoriasis skin tissue samples to confirm the increased presence of these proteins in human disease. In the skin of the psoriasis mice, investigators first identified increases in stefin A1 (342.4-fold increased; called cystatin A in humans); slc25a5 (46.2-fold increased); serpinb3b (35.6-fold increased; called serpinB1 in humans) and KLK6 (4.7-fold increased). The team found no increases of the Rab18 protein in skin tissue of the mice, and so ruled it out as a psoriasis-generating culprit. Investigators then confirmed the increased presence of the Serpinb3b, KLK6, Stefin A1, and Slc25a5 proteins in human lesional psoriasis skin tissue, and human lesional psoriasis skin cells compared to healthy control skin tissue and skin cells.
What next? The next step in pursuing this line of research for Ward’s team will be uncovering the role and significance of each of
these proteins in the progression of psoriasis.
Of the roughly 50,000 proteins in the human body, researchers have zeroed in on four that appear most likely to
contribute to this chronic disease.
January/February 2015 |
prime-journal.com
Determining the individual contributions of each protein will help provide strategic therapeutic targets to change the course of a patient’s psoriasis or, at the very least, provide a better understanding of how a change in the regulation of these proteins contributes to skin inflammation and psoriatic disease.
STUDY LINKS EXCESS IRON TO AGEING
It is well-known that iron accumulates in human tissues during ageing and toxic levels of iron have been linked to neurologic diseases, such as Parkinson’s. Common belief has held that iron accumulation happens as a result of the ageing process. But research in the nematode C. elegans in the Lithgow lab at the Buck Institute shows that iron accumulation itself may also be a significant contributor to the ageing process, causing dysfunction and malfolding of proteins already implicated in the ageing process. Similar to what happens in humans,
researchers found that levels of calcium, copper, iron, and manganese increased as worms aged. But iron accumulated much more than the others. The nematode’s diet was then changed.
‘We fed iron to four day-old worms, and within a couple of days they looked like 15 day-old worms,’ said Gordon Lithgow, PhD, senior scientist on the project. ‘Excess iron accelerated the ageing process.’ Researchers know iron generates oxidative stress and they expected to see changes in the worm based on that toxicity. ‘Instead, what we saw looked much more like normal ageing,’ said Lithgow. ‘The iron was causing dysfunction and aggregation in proteins that have already been associated with the ageing process. Now we’re wondering if excess iron also drives ageing.’ Researchers, led by graduate student
Ida Klang, also treated normal nematodes with the FDA-approved metal chelator CaEDTA—a drug that’s used in humans at risk for lead poisoning. The drug slowed age-related accumulation of iron and extended the healthspan and lifespan of the nematodes. Klang also gave the drug to worms genetically bred to develop specific protein aggregations implicated in human disease. The chelator was also protective in those animals. Lithgow says the work has implications
for the ageing research field. ‘Maintaining the proper balance of metals is key to good health throughout the lifespan, and it’s pretty obvious that this delicate balance can go off-kilter with age,’ he said.
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