Site for Alcohol's Action in the Brain Discovered
Alcohol's inebriating effects may be familiar to many, but the molecular details of its impact on brain activity remain a mystery. A new study by researchers at the Salk Institute provides a better understanding how alcohol alters the way brain cells work.
Their findings reveal an alcohol trigger site located physically within an ion channel protein; their results could lead to the development of novel treatments for alcoholism, drug addiction, and epilepsy. Paul Slesinger and his team now show that alcohols directly interact with a specific nook contained within a channel protein. This ion channel plays a key role in several brain functions associated with drugs of abuse and seizures.
Previous research by Slesinger and his group focused on the neural function of these ion channels, called GIRK channels. GIRK channels open up during periods of chemical communication between neurons and dampen the signal, creating the equivalent of a short circuit.
Having the location of a physical alcohol-binding site important for GIRK channel activation could point to new strategies for treating related brain diseases. Using this protein structure, it may be possible to develop a drug that antagonizes the actions of alcohol for the treatment of alcohol dependence.
Alternatively, "If we could find a novel drug that fits the alcohol-binding site and then activate GIRK channels, this would dampen overall neuronal excitability in the brain and perhaps provide a new tool for treating epilepsy," says Slesinger.
Why Some Tumors Don't Respond to Radiation and Chemotherapy
A tightly controlled system of checks and balances ensures that a powerful tumor suppressor called p53 keeps a tight lid on unchecked cell growth but doesn't wreak havoc in healthy cells. In their latest study, scientists at the Salk Institute suggest just how finely tuned the system is and how little it takes to tip the balance.
When unprovoked, at least two negative regulators—the related proteins Mdm2 and Mdmx—prevent p53 from unleashing its power to kill. But just slightly increasing the amount of available Mdmx, which grips p53 and renders it inactive, the Salk researchers discovered, made mice remarkably resistant to the harmful effects of radiation but very susceptible to the development of oncogene-induced lymphomas.
"Our experiments emphasize how subtle and precarious the balance is," says postdoctoral researcher and first author Yunyuan V. Wang. "A slight shift of balance and the mice survive the equivalent of Chernobyl but are in big trouble when an oncogene is activated."
Their findings could explain why some tumors don't respond to radiation or chemotherapy, and provide novel routes for the development of new anti-cancer therapies.
As a powerful tumor suppressor, p53 turns on genes that either halt cell division to allow time for repair of damaged DNA or, when all rescue attempts prove futile, to prevent cells with genetic defects from dividing, as this would fuel the development of cancer. Consequently, before any tumor cell can start proliferating willfully, it needs to escape from p53's iron fist.
"One way or another, p53 function is compromised in all cancers. Either p53 itself is mutated or there is a problem with one of the proteins that regulate p53's activity," says the study's leader Geoffrey M. Wahl, a professor in the Gene Expression Laboratory. "Our hope is that we can develop small molecule drugs that will activate p53 in those tumors where it is still functional but inactivated by one of its negative regulators."
Tumor suppressor pulls double shift as reprogramming watchdog
A collaborative study by researchers at the Salk Institute uncovered that the tumor suppressor p53, which made its name as "guardian of the genome," not only stops cells that could become cancerous in their tracks but also controls somatic cell reprogramming.
Although scientists have learned how to reprogram adult human cells such as skin cells into so-called induced pluripotent stem cells (iPSCs), the reprogramming efficiency is still woefully low. The Salk study, published in the Aug. 9 advance online edition of Nature, gives new insight into why only a few cells out of many can be persuaded to turn back the clock.
"Although we have been able to reprogram specialized cells for a while now, there had been nothing known about the control mechanisms that prevent it from happening spontaneously in the body and why it has been so hard to change their fate in a Petri dish," says Juan-Carlos Izpisúa Belmonte, a professor in the Gene Expression Laboratory, who worked closely with Geoffrey M. Wahl, also a professor in the Gene Expression Laboratory.
Their findings bring iPSCs technology a step closer to fulfilling its promise as source of patient-specific stem cells but also force scientists to rethink the development of cancer.
"There's been a decade-old idea that cancer arises through the de-differentiation of fully committed and specialized cells but eventually it was discarded in favor of the currently fashionable cancer stem cell theory," says Wahl. "Now that we know that p53 prevents de-differentiation, I believe it is time to reconsider the possibility that reprogramming plays a role in the development of cancer since virtually all cancer cells lose p53 function in one way or another."
Growth Factor Keeps Brain Development on Track
Without Fgf10 (right), neuronal stem cells fail to differentiate on time. As a result, they keep multiplying and generate a bigger pool of radial glia (shown in red).
Salk Scientists report that FGF10, a member of the firbroblast growth factor (Ffg) family of morphogens, lets brain stem cells know when it's time to get to work, ensuring they hit their first developmental milestone at the right moment.
Their findings not only add new insights into brain development and a novel function for Fgfs, but also reveal a possible mechanism for the selective expansion of specific brain areas over the course of evolution, such as the greatly increased size of the frontal lobe in humans. During embryonic brain development, stem cells in charge of building the cortex—the largest brain structure and seat of most higher cognitive functions—pass through a series of tightly regulated stages: from omnipotent stem cell to cortical progenitors cells capable of producing neurons.
"The timing of each of these transitions has critical implications for brain development, since minor changes in the proportion of progenitors exhibiting one or the other division mode at early stages will result in substantial changes in the number of neurons and the size of the cortex," says Dennis O'Leary, a professor in the Molecular Neurobiology Laboratory, who led the study.
Early in corticogenesis, stem cell-like progenitor cells known as neuroepithelial cells under go symmetric cell division, producing two identical progenitors to expand the pool of neuroepithelial cells. Later on, they differentiate into more mature progenitor cells referred to as radial glia, which then divide asymmetrically to produce a pair of unlike daughter cells: one radial glia to maintain the pool of progenitor cells and a cortical neuron or a basal progenitor. The latter will migrate outward and then produce neurons to establish the superficial layers of the cortex.
But little is known about the mechanisms that mediate the critical transition period that bridges the early expansion phase of neuroepithelial cells and the later neurogenic phase, which produces all the neurons that will eventually form the six layers of the cortex.
"These findings demonstrate a direct mechanism employed during normal development to regulate brain size," says O'Leary. "These findings also have potential implications for how cortical areas have evolved. Selectively expanding the progenitor pool by Fgf10 regulation of the timing of radial glia differentiation could account for the selective expansion of the frontal cortex, which has been greatly expanded in humans and is thought to be important for evolving what are considered typically human traits."
Nicotinic Receptor May Help Trigger Alzheimer's Disease
For close to a decade pharmaceutical researchers have been in hot pursuit of compounds to activate a key nicotine receptor that plays a role in cognitive processes. Triggering it, they hope, might prevent or even reverse the devastation wrought by Alzheimer's disease.
A new study from the Salk Institute, however, suggests that when the receptor, alpha-7, encounters beta amyloid, the toxic protein found in the disease's hallmark plaques, the two may actually go rogue. In combination, alpha-7 and beta amyloid appear to exacerbate Alzheimer's symptoms, while eliminating alpha-7 seems to nullify beta amyloid's harmful effects.
These findings, reported recently in The Journal of Neuroscience, may shed new light on the processes leading to Alzheimer's and could have important implications for researchers seeking to combat the disease.
Intrigued by earlier studies showing that beta amyloid seemed particularly drawn to the alpha-7 nicotinic receptors, researchers in the lab of Stephen F. Heinemann, in the Salk Molecular Neurobiology Laboratory, sought to determine whether the alpha-7 receptors actually modulate the effects of beta amyloid in Alzheimer's disease.
Hypothesizing that the alpha-7 nicotinic receptors mediate beta amyloid effects in Alzheimer's disease, Heinemann's team crossed mice engineered to lack the gene for alpha-7 with a mouse model for Alzheimer's disease, which had been genetically engineered to overexpress amyloid precursor protein (APP), an antecedent to beta amyloid. They then put the offspring through a series of memory tests.
Surprisingly, those with both mutations—too much APP and no gene for alpha-7—performed as well as normal mice. The Alzheimer's mice, however, which had the alpha-7 gene and also overexpressed APP, did poorly on the tests. Pathology studies revealed the presence of comparable amounts of plaques in the brains of both types of mice, but in those lacking the alpha-7 gene, they appeared to have no effect. Similar disparities were evident in measurements of the synaptic function underlying learning and memory.
"Jumping Genes" Create Diversity in Human Brain Cells
Rather than sticking to a single DNA script, human brain cells harbor astonishing genomic variability, according to Salk scientists. The findings could help explain brain development and individuality, as well as lead to a better understanding of neurological disease.
The team, led by Fred H. Gage, a professor in the Salk's Laboratory of Genetics, found that human brain cells contain an unexpected number of socalled mobile elements—extraordinary pieces of DNA that insert extra copies of themselves throughout the genome using a "copy and paste" mechanism.
"This is a potential mechanism to create the neural diversity that makes each person unique," says Gage. "The brain has 100 billion neurons with 100 trillion connections, but mobile pieces of DNA could give individual neurons a slightly different capacity from each other."
In earlier work, Gage had already shown that mobile pieces of DNA known as LINE-1 elements (short for Long interspersed element 1) randomly add extra copies to the genome of mouse brain cells. But whether or not the same process, colloquially referred to as "jumping," held true for neurons in human brains had been a matter of some debate.
When postdoctoral researcher and first author Nicole Coufal measured matched samples (brain versus other body tissues) from numerous individuals, she found that some brain samples had as many as 100 extra copies per cell.
"This was proof that these elements really are jumping in neurons," explains Coufal. Strikingly, it also means that not all cells are created equal—humans are true chimeras since the DNA in their brain cells is different from the DNA in the rest of their cells.