Home
Google
 
Home-----History-----Bibliography-----Pregnancy Timeline-----Prescription Drugs in Pregnancy-----Pregnancy Calculator-----Female Reproductive System-----News Alerts-----Contact


February, 2011---------News Archive

How Proteins Spread Neurodegenerative Disease

By Sandeep Ravindran

Misfolded proteins can get into cells and form large aggregates by recruiting normal proteins. These aggregates are associated with neurodegenerative diseases. Stanford biology Professor Ron Kopito has found that the protein linked to Huntington's can spread from one cell to another. His research may explain how these diseases spread through our brains, an understanding that might lead to the development of drugs to target the misfolded proteins.

One bad apple is all it takes to spoil the barrel. And one misfolded protein may be all that's necessary to corrupt other proteins, forming large aggregations linked to several incurable neurodegenerative diseases such as Huntington's, Parkinson's and Alzheimer's.

Stanford biology Professor Ron Kopito has shown that the mutant, misfolded protein responsible for Huntington's disease can move from cell to cell, recruiting normal proteins and forming aggregations in each cell it visits.

Knowing that this protein spends part of its time outside cells "opens up the possibility for therapeutics," he said. Kopito studies how such misfolded proteins get across a cell's membrane and into its cytoplasm, where they can interact with normal proteins. He is also investigating how these proteins move between neuronal cells.

The ability of these proteins to move from one cell to another could explain the way Huntington's disease spreads through the brain after starting in a specific region. Similar mechanisms may be involved in the progress of Parkinson's and Alzheimer's through the brain.

Kopito discussed his research Friday at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

Not all misfolded proteins are bad.

The dogma used to be that all our proteins formed neat, well-folded structures, packed together in complexes with a large number of other proteins, Kopito said. But over the past 20 years, researchers have found that as much as 30 percent of our proteins never fold into stable structures. And even ordered proteins appear to have some disordered parts.

Disordered proteins are important for normal cellular functions. Unlike regular proteins, they interact with only one partner at a time. But they are much more dynamic, capable of several quick interactions with many different proteins. This makes them ideal for a lot of the standard communication that happens within a cell for its normal functioning, Kopito said.

Professor Ron Kopito has shown that the mutant, misfolded protein responsible for Huntington's disease can move from cell to cell.

But if some of our proteins are always disordered, how do our cells tell which proteins need to be properly folded, and which don't? "It's a big mystery," said Kopito, and one that he's studying. This question has implications for how people develop neurodegenerative diseases, all of which appear to be age-related.

Huntington's disease is caused by a specific mutated protein. But the body makes this mutant protein all a person's life, so why does that person get the disease in later adulthood? Kopito said it's because the body's protective mechanisms stop doing their job as we get older. He said his lab hopes to determine what these mechanisms are.

But it's clear what happens when these mechanisms stop working – misfolded proteins start recruiting normal versions of the same protein and form large aggregations. The presence of these aggregations in neurons has been closely linked with several neurodegenerative diseases.

Kopito found that the mutant protein associated with Huntington's disease can leave one cell and enter another one, stirring up trouble in each new cell as it progresses down the line. The spread of the misfolded protein may explain how Huntington's progresses through the brain.

This disease, like Parkinson's and Alzheimer's, starts in one area of the brain and spreads to the rest of it. This is also similar to the spread of prions, the self-replicating proteins implicated in mad cow disease and, in humans, Creutzfeldt-Jakob disease. As the misfolded protein reaches more parts of the brain, it could be responsible for the progressive worsening of these diseases.

Now that we know that these misfolded proteins spend part of their time outside of cells, traveling from one cell to another, new drugs could target them there, Kopito said. This could help prevent or at least block the progression of these diseases.

Kopito is currently working to figure out how misfolded proteins get past cell membranes into cells in the first place. It is only once in the cell's cytoplasm that these proteins can recruit others. So these studies could help find ways to keep these mischief-makers away from the normal proteins.

He is also collaborating with biology Professor Liqun Luo to track these proteins between cells in the well-mapped fruit fly nervous system. In the future, Kopito said he hopes to link his cell biology work to disease pathology in order to understand the role misfolded proteins play in human disease.

Sandeep Ravindran is a science-writing intern at the Stanford News Service.

Stumbling On Key to Hair-Growth

By Enrique Rivero

It has been long known that stress plays a part not just in the graying of hair but in hair loss as well. Over the years, numerous hair-restoration remedies have emerged, ranging from hucksters' "miracle solvents" to legitimate medications such as minoxidil. But even the best of these have shown limited effectiveness.

Now, a team led by researchers from UCLA and the Veterans Administration that was investigating how stress affects gastrointestinal function may have found a chemical compound that induces hair growth by blocking a stress-related hormone associated with hair loss - entirely by accident.

The serendipitous discovery is described in an article published today in the online journal PLoS One.

"Our findings show that a short-duration treatment with this compound causes an astounding long-term hair regrowth in chronically stressed mutant mice," said Million Mulugeta, an adjunct professor of medicine in the division of digestive diseases at the David Geffen School of Medicine at UCLA and an author of the research. "This could open new venues to treat hair loss in humans through modifying stress hormone receptors, particularly hair loss related to chronic stress and aging."

The research team, which was originally studying brain–gut interactions, included Mulugeta, Lixin Wang, Noah Craft and Yvette Taché from UCLA; Jean Rivier and Catherine Rivier from the Salk Institute for Biological Studies in La Jolla, Calif.; and Mary Stenzel-Poore from the Oregon Health and Sciences University.

For their experiments, the researchers had been using mice that were genetically altered to overproduce a stress hormone called corticotrophin-releasing factor, or CRF. As these mice age, they lose hair and eventually become bald on their backs, making them visually distinct from their unaltered counterparts.

The Salk Institute researchers had developed the chemical compound, a peptide called astressin-B, and described its ability to block the action of CRF. Stenzel-Poore had created an animal model of chronic stress by altering the mice to overproduce CRF.

UCLA and VA researchers injected the astressin-B into the bald mice to observe how its CRF-blocking ability affected gastrointestinal tract function. The initial single injection had no effect, so the investigators continued the injections over five days to give the peptide a better chance of blocking the CRF receptors. They measured the inhibitory effects of this regimen on the stress-induced response in the colons of the mice and placed the animals back in their cages with their hairy counterparts.

About three months later, the investigators returned to these mice to conduct further gastrointestinal studies and found they couldn't distinguish them from their unaltered brethren. They had regrown hair on their previously bald backs.

"When we analyzed the identification number of the mice that had grown hair we found that, indeed, the astressin-B peptide was responsible for the remarkable hair growth in the bald mice," Mulugeta said. "Subsequent studies confirmed this unequivocally."

Of particular interest was the short duration of the treatments: Just one shot per day for five consecutive days maintained the effects for up to four months.

"This is a comparatively long time, considering that mice's life span is less than two years," Mulugeta said.

So far, this effect has been seen only in mice. Whether it also happens in humans remains to be seen, said the researchers, who also treated the bald mice with minoxidil alone, which resulted in mild hair growth, as it does in humans. This suggests that astressin-B could also translate for use in human hair growth. In fact, it is known that the stress-hormone CRF, its receptors and other peptides that modulate these receptors are found in human skin.

The finding is an offshoot of a study funded by the National Institutes of Health.

UCLA and the Salk Institute have applied for a patent on the use of the astressin-B peptide for hair growth.

Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines. Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, the institute is an independent nonprofit organization and architectural landmark.

The David Geffen School of Medicine at UCLA ranks among the nation's elite medical schools, producing doctors and researchers whose contributions have led to major breakthroughs in health care. With more than 2,000 full-time faculty members, nearly 1,300 residents, more than 750 medical students and almost 400 Ph.D. candidates, the medical school is ranked seventh in the country in research funding from the National Institutes of Health and third in the United States in research dollars from all sources.

Skin Color Teaches Evolution

Variations in skin color provides one of the best examples of evolution by natural selection in the human body - and should be used to teach evolution in schools, according to Penn State anthropologist.

"There is an inherent level of interest in skin color and for teachers, that is a great bonus -- kids want to know," said Nina Jablonski, professor and head, Department of Anthropology, Penn State.

Scientists have understood for years that selection of skin pigmentation is influenced by the sun.

As our human ancestors gradually lost fur to allow cooling through sweating, naked skin became directly exposed to sunlight. In the tropics, the process of natural selection favored darkly pigmented skin for protection against too much sun.

Ultraviolet B radiation produces vitamin D in human skin, but can destroy folate which is important for the rapid growth of cells. During pregnancy, folate promotes rapid cell growth and a folate deficiency can cause neural tube defects. So, the destruction of folate and deficiencies in vitamin D are evolutionary influenced as folate-deficient mothers produce fewer children who survive, and vitamin D-deficient women are less fertile than healthy women.

Dark skin pigmentation in the tropics protects people from folate destruction, allowing normal reproduction and healthy children.

In tropical zones, levels of ultraviolet B are high year round due to the intense sunlight, in response the body produces sufficient vitamin D. But humans moved out of Africa, into the subtropics and eventually up to the Arctic Circle.

North or south of 46 degrees latitude - Canada, Russia, Scandinavia, Western Europe and Mongolia - dark-skinned people cannot produce enough vitamin D, while lighter-skinned people can and thrive. Natural selection for light skin dominates.

The differences between light-skinned and dark-skinned people are more apparent to most humans than the changes in the wing color of moths or, the most commonly used evolutionary example, bacterial colonies, according to Jablonski.

Adaptation to the environment through evolutionary change becomes even more interesting when looking at the mechanism of tanning.

"In the middle latitudes tanning evolved multiple times as a mechanism to partly protect humans from harmful effects of the sun," Jablonski told attendees at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

Tanning skin evolved in humans as an adaptation to ultraviolet B radiation increases in early spring. As the sun becomes stronger, skin tans deeper. During the winter, as ultraviolet B wanes, so does the tan, allowing appropriate protection against folate destruction but sufficient vitamin D production. Skin adaptation to tanning evolved in North Africa, South America, the Mediterranean and most of China.

Natural variation in skin color due to natural selection can be seen in nearly every classroom in the U.S. as humans now move around the globe far faster than evolution can adjust their skin color for the sun.

The idea that variation in skin color is due to where one's ancestors originated and how strong the sun was in those locations is inherently interesting, Jablonski noted.

"People are really socially aware of skin color, intensely self-conscious about it," she said. "The nice thing about skin color is that we can teach the principles of evolution using an example on our own bodies and relieve a lot of social stress about personal skin color at the same time."

Jablonski noted that the ability to tan developed in a wide variety of peoples and while the tanablity outcome, is the same, the underlying genetic mechanisms are not necessarily identical.

She also notes that depigmentated skin also developed at least three times through different genetic mechanisms. Students who never tan, can now understand why they don't and never will.

Macho Muscle Cells Force Their Way Into Fusion

Muscle, aptly enough, is born of cellular bullying, and not mutual consent.

In fact, according to new research from Johns Hopkins University, the fusion of muscle cells is a power struggle that involves a smaller mobile antagonist that points at, pokes and finally pushes into its larger, stationary partner using a newly identified finger-like projection.

In a report published Nov. 29 in the Journal of Cell Biology, the researchers described experiments using fruit fly embryos to identify an invasive projection propelled by the rapid elongation of actin filaments as the main player in the cellular power struggle.

“We found that two muscle cells don’t simply open up their membranes and symmetrically fuse together,” says Elizabeth H. Chen, Ph.D., an assistant professor in the department of molecular biology and genetics, Johns Hopkins University School of Medicine. “Muscle cell fusion is actually an invasive battle.”

Before the new study, it was assumed that actin-enriched blobs sit atop the membranes of muscle cells preparing to fuse, equally dispersed.

But by observing the accumulation of these blobs using genetic tools, the team concluded that the actin structure is produced in only one of the two muscle cell types - the aggressive fusion-competent myoblast - and not in the stationary founder cell. Further analyses of the images, made with an electron microscope, showed the myoblast is extending multiple finger-like protrusions toward founder cells and ultimately forcing fusion with the founder cell by forming an open pore.

“Where we once saw only blobs of actin, now we could clearly see finger-like protrusions emanating from one cell into another,” Chen says. “That really helped us make the connection between this structure and invasive podosomes.”

The new work shows what is believed to be the first time that an invasive podosome-like structure has been found in developing tissue of any kind, Chen says, noting that although podosomes were discovered several decades ago in studies of cells growing in dishes, they have not been seen in a developing animal or implicated as a mechanism in cell fusion.

“It may be that this new understanding of muscle cell fusion will apply generally to other cells that fuse,” Chen says, “such as egg and sperm, for instance, as well as bone resorption cells and cells that are vital for immune responses.”

Muscle fusion is an integral part of muscle regeneration in genetic and acquired muscle diseases, and an accurate understanding of this basic cellular event could have important clinical applications in people with muscular dystrophy and other degenerative disorders, according to Chen.

The research was supported by the National Institutes of Health and the American Heart Association.

In addition to Elizabeth Chen, authors on the paper are Kristin L. Sens, Shiliang Zhang, Peng Jin, Rui Duan, Fengbao Luo and Lauren Parachini, all of Johns Hopkins; and Guofeng Zhang of the National Institute of Biomedical Imaging and Bioengineering.















Care.com





Home---History- --Bibliography- -Pregnancy Timeline---Prescription Drugs in Pregnancy--- Pregnancy Calculator----Female Reproductive System---News Alerts---Contact-
Creative Commons LicenseContent protected under a Creative Commons License. No dirivative works may be made or used for commercial purposes.