Posts tagged cell death
Articles and news from the latest research reports.
Microglia controls neuron production as brain develops
In a surprise breakthrough, researchers at the UC Davis MIND Institute and their colleagues have found that microglia remove healthy neural progenitor cells (NPCs) through phagocytosis to control neuron production during brain development. This newly discovered mechanism keeps neuron numbers in check, preventing brain overgrowth.
The discovery could open up new avenues for brain research and lead to therapies for a variety of neurological conditions.
The study was published online in the The Journal of Neuroscience.
Microglia are the immune component cell of the central nervous system. Similar to macrophages, microglia provide the brain’s primary defense against pathogens and foreign bodies, clear away dying cells and help repair neural damage. When inactive, they act as sentinels. When a problem is located, they activate and eliminate it. However, until recently, no one had realized the important roles they play in brain development.
"We have known for some time that neurons can undergo apoptosis, a form of cell death, and ultimately be removed by microglia," said Stephen Noctor, assistant professor in the Department of Psychiatry and Behavioral Sciences and the study’s lead author. "But this is new. Microglia are actually eating healthy progenitor cells, thereby regulating the number of neurons produced in the developing brain."
During development, NPCs produce neurons in the brain’s proliferative zones. However, creating too many or too few neurons can have dire consequences.
"If you have too many cells, there’s only so much trophic support (brain infrastructure for cell growth and survival) to keep neurons alive," Noctor said. "All these cells competing for resources could easily throw off connectional properties, altering the way surviving neurons interact. Likewise, having too few cortical cells would have profoundly negative consequences."
(Image: Antoine Triller, Alain Bessis & Serge Marty - Département de Biologie, ENS)
Identification of abnormal protein may help diagnose, treat ALS and frontotemporal dementia
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective treatment. Researchers are beginning to recognize ALS and FTD as part of a spectrum disorder with overlapping symptoms. Now investigators reporting online February 12 in the Cell Press journal Neuron have discovered an abnormal protein that first forms as a result of genetic abnormalities and later builds up in the brains of many patients with either disease.
"In identifying the novel protein that abnormally accumulates in the brains of affected patients, we have uncovered a potentially new therapeutic target and biomarker that would allow clinicians to confirm diagnosis of the diseases," says senior author Dr. Leonard Petrucelli, Chair of Neuroscience at Mayo Clinic in Florida.
By analyzing brain tissue from patients with ALS or FTD, Dr. Petrucelli and his team discovered that the abnormal protein, which they call C9RANT, is generated as a result of repeat expansions of nucleotides in the noncoding region of the C9ORF72 gene. These expansions are the most common cause of ALS and FTD. “Simply put, an error in the highly regulated cellular process through which proteins are generated causes the abnormal production of C9RANT,” explains Dr. Petrucelli.
The researchers discovered the protein C9RANT after creating a novel antibody to specifically detect it. The ability to detect C9RANT in individuals’ cerebrospinal fluid may provide a valuable diagnostic and prognostic tool for identifying patients carrying the C9ORF72 repeat expansion and for then tracking the progression of the disease in these at-risk individuals.
"Although it remains to be shown whether C9RANT is causing the cell death or toxicity associated with disease symptoms, our discovery offers a potential target to prevent neuronal loss in patients carrying the C9ORF72 repeat expansion," says Dr. Petrucelli.
The concept that abnormal proteins accumulate and can be toxic to cells is not new. In fact, tau protein forms tangles in Alzheimer’s disease and alpha-synuclein forms clumps in Parkinson’s disease. Just as new therapies are being developed to break down the protein aggregates associated with these diseases, developing a therapeutic strategy to target C9RANT aggregates may also prove beneficial.
UGA discovery sheds light on Alzheimer’s mystery
In 1906, when Alois Alzheimer discovered the neurodegenerative disease that would later be named for him, he saw amyloid-beta plaques and neurofibrillary tangles inside the brain. Several decades later, abnormal protein structures called Hirano bodies also were frequently observed in patients with neurodegenerative diseases.
A hundred years and many millions of suffering patients and families later, scientists still don’t know what these structures do. They do know, thanks to new research from the University of Georgia, that Hirano bodies may have a protective role in the brain of Alzheimer’s patients.
Matthew Furgerson, a doctoral candidate in the UGA Franklin College of Arts and Sciences department of biochemistry and molecular biology, used cell culture models to study the role of Hirano bodies in cell death induced by AICD, or a fragment of AICD called c31, that are released inside the cell during cleavage of the amyloid precursor protein. This cleavage also produces amyloid-beta, which forms extracellular plaques.
Furgerson found mixtures of amyloid precursor protein, c31 and tau-the protein that forms the intracellular neurofibrillary tangles-or of AICD and tau cause synergistic cell death that is significantly higher than cell death from amyloid precursor protein, c31, AICD or tau alone.
"This synergistic cell death is very exciting," Furgerson said. "Other groups have shown synergy between extracellular amyloid beta or amyloid precursor protein with tau, but these new results show that there may be an important interaction that occurs inside the cells."
The results of this study were published in the September issue of PLoS One. Ruth Furukawa, associate research scientist, and Marcus Fechheimer, University Professor in cellular biology, are co-authors on the paper.
Furgerson also found cell death is significantly reduced in cells that contain Hirano bodies compared to cells without Hirano bodies. The protective effect of Hirano bodies was observed in cell cultures in both the presence and absence of tau. The findings reveal that Hirano bodies may have a protective role during the progression of Alzheimer’s disease.
While this research offers no cure for the disease, it does offer some understanding about how the disease operates. The lab has been a leader of Hirano body research for more than a decade due to their development of cell culture and mouse model systems.
Before the development of model systems, the only way to study these abnormal structures was in post-mortem brain tissue. The recently developed Hirano body mouse model is currently being used with an Alzheimer’s model mouse to investigate whether cell culture results can translate to a complex animal.
"I feel privileged to lead a team that might be able to contribute knowledge to help us understand Alzheimer’s disease processes," Fechheimer said. "Other groups have focused on plaques and tangles, and we don’t know as much about Hirano bodies. Results from the cell culture studies are exciting and reveal the protective role of Hirano bodies. Our ongoing studies with mouse models are essential to defining the role of Hirano bodies in Alzheimer’s disease progression in a whole animal."
(Source: news.uga.edu)
Potential new class of drugs blocks nerve cell death
Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures.
Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).
“We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need,” says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies.
About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3.
“We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging,” Pieper explains. “We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus.”
However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease.
Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice.
(Source: now.uiowa.edu)
Giving lithium to those who need it
Lithium is a ‘gold standard’ drug for treating bipolar disorder, however not everyone responds in the same way. New research published in BioMed Central’s open access journal Biology of Mood & Anxiety Disorders finds that this is true at the levels of gene activation, especially in the activation or repression of genes which alter the level the apoptosis (programmed cell death). Most notably BCL2, known to be important for the therapeutic effects of lithium, did not increase in non-responders. This can be tested in the blood of patients within four weeks of treatment.
A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.
Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, “We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis).”
For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.
The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.
Dr Beech continued, “This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future.”
(Source: biomedcentral.com)
The most common form of strokes are caused by a sudden reduction in blood flow to the brain (ischemia) that leads to an inadequate supply of oxygen and nutrients. These so-called ischemic strokes are one of the leading causes of death and disability in industrialized nations. If they are not immediately remedied by medical intervention, areas of the brain may die off. In the journal Angewandte Chemie, Korean researchers have now proposed a new approach for supplemental treatment: Ceria nanoparticles could trap the reactive oxygen compounds that result from ischemia and cause cells to die.
Neural precursor cells induce cell death in certain brain tumors
July 23, 2012
Neural precursor cells (NPC) in the young brain suppress certain brain tumors such as high-grade gliomas, especially glioblastoma (GBM), which are among the most common and most aggressive tumors. Now researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin have deciphered the underlying mechanism of action with which neural precursor cells protect the young brain against these tumors. They found that the NPC release substances that activate TRPV1 ion channels in the tumor cells and subsequently induce the tumor cells to undergo stress-induced cell-death. (Nature Medicine http://dx.doi.org/10.1038/nm.2827)*.
Despite surgery, radiation or chemotherapy or even a combination of all three treatment options, there is currently no cure for glioblastoma. In an earlier study the research group led by Professor Helmut Kettenmann (MDC) showed that neural precursor cells migrate to the glioblastoma cells and attack them. The neural precursor cells release a protein belonging to the family of BMP proteins (bone morphogenetic protein) that directly attacks the tumor stem cells. The current consensus of researchers is that tumor stem cells are the actual cause for continuous tumor self-renewal.
Kristin Stock, Jitender Kumar, Professor Kettenmann (all MDC), Dr. Michael Synowitz (MDC and Charité), Professor Rainer Glass (Munich University Hospitals, formerly MDC) and Professor Vincenzo Di Marzo (Istituto di Chimica Biomolecolare Pozzuoli, Naples, Italy) now report a new mechanism of action of NPC in astrocytomas. Like glioblastomas, astrocytomas are brain tumors that belong to the family of gliomas. Gliomas are most common in older people and are almost invariably fatal.
As the MDC researchers showed, the NPC also migrate to the astrocytomas. There they do not secrete proteins, but rather release fatty-acid substances (endovanilloids) which are harmful to the cancer cells. However, in order to exert their lethal effect, the endovanilloids need the aid of a specific ion channel, the TRPV1 channel (transient receptor potential vanilloid type 1), also called the vanilloid receptor 1. TRPV1 is already known to researchers as a transducer of painful stimuli. It has, among other things, a binding site for capsaicin, the irritant of hot chili peppers, and is responsible for the hot sensation after eating them. Clinical trials are currently underway to develop new pain treatments by blocking or desensitizing this ion channel.
MDC researchers describe an additional role of the TRPV1 ion channel
In contrast to its use in pain management, this ion channel, which is located on the surface of glioblastoma cells and is much more abundant there than on normal glial cells, must be activated to trigger cell death in gliomas. The activated ion channel mediates stress-induced cell-death in tumor cells. If however TRPV1 is downregulated or blocked, the glioma cells are not destroyed. The MDC researchers are thus the first to identify neural precursor cells as the source of fatty acids that induce tumor cell death and to describe the role of the TRPV1 ion channel in the fight against gliomas.
However, the activity of neural precursor cells in the brain and thus of the body’s own protective mechanism against gliomas diminishes with increasing age. This could explain why these tumors usually develop in older adults and not in children and young people. How can the natural protection of neural precursor cells be harnessed for older brains? According to the researchers, neural precursor cell therapy is not a solution. The benefit this obviously brings in the treatment of young people can have the opposite effect in older adults and may trigger brain tumors.
One possible treatment would be to use drugs to activate the TRPV1 channels. In mice, the group showed that a synthetic substance (arvanil), which is similar to capsaicin, reduced tumor growth. However, this substance has not yet been approved as a drug because the adverse side effects for humans are too severe. It is only used in basic research on mice, which tolerate the substance well. “In principle, however,” the researchers suggest, “synthetic vanilloid compounds may have clinical potential for brain tumor treatment.”
Source: Science Codex