Researchers at the University of Chicago have found that a recently discovered biological process known as sumoylation (SUMO)—until now thought to be active only in the nucleus—also occurs near the cell’s surface where it regulates at least one and possibly many kinds of proteins, providing a novel target for the development of new drugs.

The discovery, published in the 8 April 2005 issue of Cell, answers a question dating back to the 1950s: How do cells control the background movement of potassium ions across the cell membrane? This process is important because the flow of potassium ions determines whether “excitable” cells in the brain, heart and skeletal muscles “fire,” sending out nervous impulses that become thoughts, heartbeats and basketball dunks.

“We found that a little-studied process called sumoylation, previously associated with nuclear proteins, is alive and essential outside the nucleus at the plasma membrane,” says Steve Goldstein, M.D., Ph.D., Professor and Chair, Department of Pediatrics and Director of the Institute for Molecular Pediatric Sciences. “This adds a new chapter to the book of how cells control ion channel function: reversible peptide linkage.”

Ion channels are in every cell of the human body. They are tightly controlled tunnels through the membrane barriers that hold in the cell’s contents, separating the cell from the outside world. Ion channels allow ions such as potassium, sodium and calcium to flow in and about and so are key regulators of many fundamental processes in biology.

He adds that, “Cellular solvency, the ability to respond to the stimuli that are life, is all about the balance between ions inside and outside each cell. The gradual doling out or sudden influx of ions through ion channels are the basis for those cellular activities that give us thoughts, sights, tastes, sounds and our ability to move.”

“Consequently, cells control these actions as carefully as we watch our finances, which is why so many of the most potent medications we use to care for our patients target one or another ion channel,” Goldstein explains.

Sumoylation has recently been recognized as an important mechanism of cellular activity but until now its 60-or-so known targets were primarily nuclear proteins, mostly involved in gene transcription. “The findings expand the influence of SUMO-related activity in biology," says Goldstein, "which is a great and exciting surprise."

An enriched environment, in the form of running wheels, colorful tunnels and assorted toys may hold the key to preventing the onset of Alzheimer's disease, the major cause of adult-onset dementia. At least, it seems to play a role in preventing the onset of Alzheimer's disease pathology in mice, which in turn may lead researchers to identify similar ways to slow the process down in humans.

Alzheimer's disease is associated with deposition of b-amyloid (Ab) peptides and neuron loss in the cerebral cortex and hippocampal formation. Using evidence suggesting that the hippocampus and cortex are directly impacted by environmental factors throughout life, Sangram Sisodia, Ph.D., Thomas Reynolds Sr. Family Professor of Neurosciences, Department of Neurobiology, Pharmacology & Physiology, and his team established a fairly simple model to test the impact of both “enriched” and “standard” housing environments on Ab deposits in mice.

“This is the first demonstration in a genetically clean, carefully controlled animal model showing that an enriched environment can have such a tremendously beneficial impact, protecting the brain from the pathological hallmarks of this insidious disease,” Sisodia explains.

The findings were published in the 11 March 2005 issue of Cell and demonstrate for the first time the timeline of connectivity between physical and mental stimulation and the delay in the onset of Alzheimer's.
“We have plenty of epidemiological evidence connecting activity, exercise and education with later onset of Alzheimer's, but it has never been clear which came first,” says Sisodia. “Did the active lifestyle delay disease, or was there something inherent in a disease-resistant brain that led to a mentally and physically active lifestyle?”

Sisodia and colleagues from his lab—Orly Lazarov, Ph.D., Research Associate (Assistant Professor), Neurobiology, Pharmacology & Physiology and John Robinson, Senior Research Technician—found that the mice who were not only in the enriched environments but who also utilized that environment most -- spending time on the running wheels -- exhibited the most significant reduction in amyloid burden, indicating that exercise may play a key role in modulating amyloid deposition. Additionally, these mice showed greater activity for the growth of new nerve cells, cell survival and growth of new blood vessels within the brain, something Sisodia suspects may be key in preventing the onset of Alzheimer's disease.

“It may be all about blood flow,” postulates Sisodia. “We suspect a large part of this process is the growing inability of mice, or people, who are developing Alzheimer's to get rid of the substances that comprise amyloid deposits, to slice up the peptides, sweep them into the blood stream and ship them out of the brain.”

Ultimately, Sisodia encourages people to take these findings to heart earlier rather than later. “Activity helps, physical and mental, and the earlier you begin the better, a troubling notion in an increasingly inactive society,” Sisodia cautions. “This is prevention, not therapy.”

 

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