Posts tagged disease

Article Date: 14 Feb 2012 - 1:00 PST

Researchers at the Salk Institute have discovered a startling feature of early brain development that helps to explain how complex neuron wiring patterns are programmed using just a handful of critical genes. The findings, published in Cell, may help scientists develop new therapies for neurological disorders, such as amyotrophic lateral sclerosis (ALS), and provide insight into certain cancers.

The Salk researchers discovered that only a few proteins on the leading edge of a motor neuron’s axon - its outgoing electrical “wire” - and within the extracellular soup it travels through guide the nerve as it emerges from the spinal cord. These molecules can attract or repel the axon, depending on the long and winding path it must take to finally connect with its target muscle.

“The budding neuron has to detect the local environment it is growing through and decide where it is, and whether to grow straight, move to the left or right, or stop,” says the study’s senior investigator, Sam Pfaff, a professor in Salk’s Gene Expression Laboratory and a Howard Hughes Medical Institute investigator.

“It does this by mixing and matching just a handful of protein products to create complexes that tell a growing neuron which way to go, in the same way that a car uses the GPS signals it receives to guide it through an unfamiliar city,” he says.

The brain contains millions of times the number of neuron connections than the number of genes found in the DNA of brain cells. This is one of the first studies to try and understand how a growing neuron integrates many different pieces of information in order to navigate to its eventual target and make a functional connection.

“We focused on motor neurons that control muscle movements, but the same kind of thing is going on throughout embryonic development of the entire nervous system, during which millions of axons make trillions of decisions as they move to their targets,” he says. “It is the exquisite specificity with which they grow that underlies the basic architecture and proper function of the nervous system.”

These findings might eventually shed new light on a number of clinical disorders related to faulty nerve cell functioning, such as ALS, which is also known as Lou Gehrig’s disease, says the first author on the paper, Dario Bonanomi, a post-doctoral researcher in Pfaff’s laboratory.

“These are the motor neurons that die in diseases like Lou Gehrig’s disease and that are linked to a genetic disorder in children known as spinal muscle atrophy,” Bonanomi says.

“It is also a jumping off point to try and understand the basis for defects that might arise during fetal development of the nervous system,” he added. “A better understanding of those signals might help to be able to regenerate and rewire circuits following diseases or injuries of the nervous system.”

The researchers say the study also offers insights into cancer development, because a protein the researchers found to be crucial to the “push and pull” signaling system - Ret- is also linked to cancer. Mutations that activate Ret are linked to a number of different kinds of tumors.

The other protein receptors described in the study, known as Ephs, have also been implicated in cancer, Pfaff says.

“This study suggests that the way cells detect signals in their environment is likely a universal strategy,” he says, “and we know that genes and proteins known to function primarily during embryonic development have been linked to cancer.”

“Controlling neuronal growth requires very potent signaling molecules, and it makes sense they would be linked to disease,” Pfaff says. “We hope our findings help further unravel these connections.”

Source: Medical News Today 

ScienceDaily (Feb. 3, 2012) — One of the big mysteries in biology is why cells age. Now scientists at the Salk Institute for Biological Studies report that they have discovered a weakness in a component of brain cells that may explain how the aging process occurs in the brain.

This microscope image shows extremely long-lived proteins, or ELLPs, glowing green on the outside of the nucleus of a rat brain cell. DNA inside the nucleus is pictured in blue. The Salk scientists discovered that the ELLPs, which form channels through the wall of the nucleus, lasted for more than a year without being replaced. Deterioration of these proteins may allow toxins to enter the nucleus, resulting in cellular aging. (Credit: Courtesy of Brandon Toyama, Salk Institute for Biological Studies)

The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan.

While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism, a finding they reported February 3 in Science.

The Salk scientists are the first to discover an essential intracellular machine whose components include proteins of this age. Their results suggest the proteins last an entire lifetime, without being replaced.

ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. Unlike other proteins in the body, ELLPs are not replaced when they incur aberrant chemical modifications and other damage.

Damage to the ELLPs weakens the ability of the three-dimensional transport channels that are composed of these proteins to safeguard the cell’s nucleus from toxins, says Martin Hetzer, a professor in Salk’s Molecular and Cell Biology Laboratory, who headed the research. These toxins may alter the cell’s DNA and thereby the activity of genes, resulting in cellular aging.

Funded by the Ellison Medical Foundation and the Glenn Foundation for Medical Research, Hetzer’s research group is the only lab in the world that is investigating the role of these transport channels, called the nuclear pore complex (NPC), in the aging process.

Previous studies have revealed that alterations in gene expression underlie the aging process. But, until the Hetzer lab’s discovery that mammals’ NPCs possess an Achilles’ heel that allows DNA-damaging toxins to enter the nucleus, the scientific community has had few solid clues about how these gene alterations occur.

"The fundamental defining feature of aging is an overall decline in the functional capacity of various organs such as the heart and the brain," says Hetzer. "This decline results from deterioration of the homeostasis, or internal stability, within the constituent cells of those organs. Recent research in several laboratories has linked breakdown of protein homeostasis to declining cell function."

The results that Hetzer and his team just report suggest that declining neuron function may originate in ELLPs that deteriorate as a result of damage over time.

"Most cells, but not neurons, combat functional deterioration of their protein components through the process of protein turnover, in which the potentially impaired parts of the proteins are replaced with new functional copies," says Hetzer.

"Our results also suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs," he adds.

The findings may prove relevant to understanding the molecular origins of aging and such neurodegenerative disorders as Alzheimer’s disease and Parkinson’s disease.

In previous studies, Hetzer and his team discovered large filaments in the nuclei of neurons of old mice and rats, whose origins they traced to the cytoplasm. Such filaments have been linked to various neurological disorders including Parkinson’s disease. Whether the misplaced molecules are a cause, or a result, of the disease has not yet been determined.

Also in previous studies, Hetzer and his team documented age-dependent declines in the functioning of NPCs in the neurons of healthy aging rats, which are laboratory models of human biology.

Hetzer’s team includes his colleagues at the Salk Institute as well as John Yates III, a professor in the Department of Chemical Physiology of The Scripps Research Institute.

When Hetzer decided three years ago to investigate whether the NPC plays a role in initiating or contributing to the onset of aging and certain neurodegenerative diseases, some members of the scientific community warned him that such a study was too bold and would be difficult and expensive to conduct. But Hetzer was determined despite the warnings.

Source: ScienceDaily