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Alzheimers Disease

Alzheimers Disease

Alzheimers Disease

Description
Alzheimer's disease is a physical illness that causes changes in the brain. It is a form of dementia. Dementia affects a person's memory, mood, and behavior. A person with Alzheimer's disease has trouble remembering, speaking, learning, making judgments, and planning. Some people feel restless and moody. Alzheimer's disease is a progressive, irreversible brain disorder with no known cure. It may take years for Alzheimer's disease to get worse. No one knows what causes Alzheimer's disease. We do know physical changes take place in the brain. Always fatal, Alzheimer's disease is the most common form of irreversible dementia.

Who is at Risk?
Alzheimer's disease usually affects people over 65. About 5 in 100 people have Alzheimer's at age 65. By age 80, these odds increase to 1 in 5. By age 90, nearly half of all people have some symptoms of dementia. Women are more likely to develop the disease than men are – in part, because women live longer. Alzheimer's disease can develop in people under the age of 50, but it is very rare. Family history is a key risk factor for Alzheimer's disease. People who have a brother, sister, or parent with Alzheimer's disease have a slightly higher chance of developing it themselves. Only 3% of all cases have a proven hereditary link. Heredity plays a much larger role in early-onset (before age 65) Alzheimer's.

Sources: Novartis Pharmaceuticals Corporation, American Health Assistance Foundation

TSRI Professor Studies Cellular and Molecular Interactions and Cognition in Quest for Useful Therapeutics
TSRI Professor Tamas Bartfai, Ph.D., who holds the Harold L. Dorris Chair in Neuroscience and directs the Harold L. Dorris Neurological Research Center, is studying the association of cellular and molecular mechanisms to the phenomenon of cognition, specifically identifying the molecular correlates of changes in long-term memory and emotional states. Bartfai hopes to turn these basic observations into useful therapeutics to counter degenerative diseases like Alzheimer's disease.

Bartfai's work on the neuropeptide galanin has led to three galanin receptors becoming the target of more than 20 projects in the pharmaceutical industry. He was also recently honored with a Distinguished Investigator Award by the National Alliance for Research on Schizophrenia and Depression, the largest non-governmental organization funding brain research worldwide.

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A Beneficial Link Between a Nicotine Metabolite and Alzheimer's Disease
TSRI Professor Kim Janda, Ph.D., Ely R. Callaway Chair in Chemistry, has discovered that a chemical called nornicotine, a metabolite which occurs in tobacco products, modifies proteins that misfold and form the fibril plaques that are abundant in the brains of patients with Alzheimer's disease. Nornicotine seems to prevent the aggregation of amyloid beta proteins, and, thus, could potentially impact the onset of Alzheimer's disease.

The research is promising because it demonstrates how one small molecule can cause a chemical interaction that may alter a mechanism important in Alzheimer's disease. This could lead to the development of small molecules similar to nornicotine that are not toxic, but could behave in a similar fashion – and prevent the aggregation of amyloid beta protein and perhaps treat Alzheimer's disease.

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TSRI Scientists Discover a Therapeutic Strategy for "Misfolding Diseases" Analogous to Alzheimer's Disease
Professor Jeffery W. Kelly, Ph.D., Lita Annenberg Hazen Professor of Chemistry, and his colleagues, have uncovered a potentially useful strategy to treat the rare disease familial amyloid polyneuropathy (FAP) – an approach that may be generally useful for intervention in other amyloid diseases. The team demonstrated that it is possible to prevent the protein shape changes that cause FAP, a disease that is analogous to Alzheimer's. The strategy is to introduce another protein that interacts with the protein capable of aberrant shape changes, preventing them. Amyloid-forming diseases like FAP are generally characterized by the formation of microscopic fibrils made up of hundreds of misfolded proteins that cluster together and deposit in organs, interfering with their normal function. These fibrils cause the disease FAP by building up around the peripheral nerve and muscle tissue, disrupting their function and leading to numbness and muscle weakness, and – in advanced cases – failure of the gastrointestinal tract.

Kelly and his colleagues discovered that a "suppressor" protein transthyretin (TTR) subunit incorporated into a TTR tetramer with disease-associated destabilizing subunits prevents the tetramer from dissociating into potential fibril-forming monomers. Significantly, they found that incorporating even one of the suppressor subunits into a tetramer where the remainder of the subunits have disease associated mutations doubles its stability. The suppressor protein subunits prevent misfolding by preventing dissociation. This "trans" suppression approach may form the basis for a new therapy in FAP, in which a patient could receive an injection of the suppressor protein. When gene therapy becomes practical, one may be able to introduce the suppressor gene directly into the organ that makes the aberrant protein. The protective subunit will therefore be incorporated during biosynthesis, thus preventing later misfolding.

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Preventing Neurodegenerative Diseases
One of the unanswered questions in the field of neuroscience has been how neurons in the brain develop and form connections – sometimes as many as 10,000 apiece. This question is of great interest to scientists because neurons are irreversibly damaged or lost in spinal cord injuries and neurodegenerative diseases like Alzheimer's. TSRI Associate Professor Shelley Halpain, Ph.D. and several of her colleagues report progress in this area. What the researchers were asking in particular was how two different neuronal proteins help maturing neurons send out neurites – the long finger-like processes characteristic of mature neurons that connect them with other neurons. The microtubules and actin filaments – the cell's cytoskeleton – must assemble at the same time for the proper formation of the neurites. Scientists have identified a number of proteins that mediate this interaction, including the microtubule-associated proteins MAP2 and tau. MAP2 and tau are abundant in neurons where they stabilize and promote the growth of the microtubules – something needed for neurite outgrowth. Halpain and her colleagues found that MAP2 is sufficient to trigger neuritic growth, but tau is not. And by making a "chimeric" protein of tau with one piece of MAP2 exchanged (the piece that binds to actin), Halpain showed that this altered tau could now induce neurites.

These differences between MAP2 and tau may cause scientists to rethink the role of tau in neurons and in various neurological disorders. For a long time, scientists have known that tau proteins form abnormal aggregates inside cells in Alzheimer's disease, even though the amyloid proteins that form plaques outside of cells were thought to be the actual cause of the disease. Nevertheless, several other diseases are now known to result directly from defective tau – these are called tauopathies. These rare hereditary dementias, which were just discovered in the last decade, are caused by single amino acid mutations in tau that cause the protein to form fibrous "neurofibrillary" tangles inside neurons. Interestingly, no such mutations have been found to cause the MAP2 protein to form tangles. Perhaps the ability of MAP2 to interact with actin as well as microtubules may prevent it from forming neurofibrillary tangles. Such information may be used in the future to determine how altering tau's structure could prevent neurodegenerative diseases.

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Analyzing the Physiological Processes that Underlie Alzheimer's Disease
The goal of TSRI Assistant Professor Thomas Krucker, Ph.D.'s laboratory is to elucidate physiological processes that underlie neuronal degeneration in diseases such as Alzheimer's disease and senile dementia using mutant mice as models. Krucker and his colleagues are using functional assays to directly assess cognitive performance (electrophysiological and behavioral methods). They combine these assays with in vivo and ex vivo imaging. As a completely unique approach, they are using novel techniques to study the architecture and morphology of the brain vasculature including microvessels and capillaries.

Krucker's studies have enabled him to characterize the time-dependent consequences of neurophysiological and neuropharmacological alterations, and test pharmacological interventions. Based on his recent findings, he suggests that time-lapsed non-invasive imaging of temporal alterations in brain vasculature morphology and architecture could be used as a diagnostic tool for Alzheimer's disease and to monitor therapies.

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A Protein That Affects The Shape Of Neurons
A century ago, much of the cutting-edge research in mental health was directed at understanding the psychological basis of psychiatric diseases: how memories and experiences play a role in our mental states. From this research emerged behavioral therapy, Freudian analysis, group therapy, and many other techniques that have been successfully applied to treatment in the field of mental health. Today, as we understand more and more about how the human body and the brain work on the cellular and molecular level, there is more interest than ever in the physiological basis for psychiatric diseases—the systems of interacting molecules and the chemical mechanisms through which these diseases manifest themselves. The reason for this interest is simple: there is an overwhelming need. According to the National Institute of Mental Health, over one fifth of all Americans -- more than 44 million individuals -- suffer from a diagnosable mental disorder in any given year. Now two scientists at The Scripps Research Institute are reporting a breakthrough in our understanding of the brain physiology that forms the basis for certain psychiatric diseases. In a recent issue of the journal Neuron, Associate Professor Shelley Halpain, Ph.D., and Research Associate Barbara Calabrese, Ph.D., describe how a protein called MARCKS affects the shape of neurons, particularly the part of the neurons known as dendritic spines, which are essential for learning and memory.

Because dendritic spines are so central to mental functioning, it's no surprise they are associated with neurological and psychiatric diseases. In mental retardation and autism, for instance, the shape of the dendritic spines are different. Under a microscope, the dendritic spines of many mentally retarded people are longer and appear more immature. In recent years, scientists have become increasingly aware of the possibility that a number of psychiatric and neurodegenerative diseases like Alzheimer's are also affected by synaptic changes brought about by spine morphology. The brains of schizophrenic patients or people suffering from mood disorders also show a reduced number of dendritic spines in the brain areas associated with these diseases. In the paper, the researchers show that MARCKS is a key player in the brain that affects the shape of these critical parts of human neurons. The research suggests a potential link between the molecular mechanisms involving MARCKS and the synaptic dysfunction observed in neurological diseases. MARCKS has a profound effect on already established, mature neurons. This type of altered neuronal morphology is one of the primary interests of Halpain and her laboratory. She and her colleagues have been developing and applying tools to study how synaptic connections are formed during the development of an organism, for instance, and to what extent they are altered or lost in certain diseases. The hope is that by understanding the biology of destabilization we can improve upon therapies that restore synapses.

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Scientists Discover Small Molecule That Generates Neurons From Adult Stem Cells
A group of scientists from The Scripps Research Institute and the Salk Institute for Biological Studies have uncovered a synthetic small molecule that generates functional neurons from adult neural stem cells. The molecule, named neuropathiazol, selectively and potently induces neuronal differentiation of neural stem or progenitor cells. The results of this study may ultimately help in the development of future small molecule therapeutics that could stimulate the regeneration of neurons in patients suffering from neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, or brain injuries. The study was led by Sheng Ding, Ph.D., an assistant professor in the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology.  Co-authors included TSRI investigator Peter G. Schultz, Ph.D. Stem cells have huge potential in medicine because they have the ability to differentiate into many different cell types—potentially providing doctors with the ability to produce cells that have been permanently lost by a patient. For instance, the damage of neurodegenerative diseases like Parkinson's, in which dopaminergic neurons in the brain are lost, may be ameliorated by regenerating neurons. However bright the promise of this type of therapy, many barriers must be overcome before stem cells can be used in medicine. Scientists have yet to understand the natural signaling mechanisms that control stem cell fate and to develop ways to manipulate these controls.

The research team led by Ding has been taking a discovery approach to finding small molecules that can control stem cell fate. Previously, the scientists reported discoveries of various small molecules that can turn embryonic stem cells into neurons or cardiac muscle cells; turn mesenchymal stem cells into bone cells; and induce a cell to undergo dedifferentiation, moving cells backwards developmentally from its current state to form its own precursor cell. As part of this effort, Ding and his colleagues have created extensive chemical and genomic libraries. In fact, their combinatorial chemical library contains more than 100,000 discrete and diverse bioactive small molecules, and high throughput screening uses various automated assays to search such large numbers of substances for a specific activity. For the current study, the researchers tested tens of thousands of small molecules in the process of identifying neuropathiazol, which they found can highly selectively turn more than 90 percent of primary adult hippocampal neural progenitors into neurons in tissue culture. The researchers believe this study provides an important step forward, opening new avenues to understanding how to control neural stem cell fate.

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Study Reveals Unusual Structure Of Cellular Transport Nanocage
A new study by scientists at The Scripps Research Institute has revealed for the first time the structure of Sec13/31, a "nanocage" that transports a large body of proteins from the endoplasmic reticulum (ER), which makes up more than half the total internal cell membrane, to other regions of the cell. The newly uncovered structure of the Sec13/31 cage reveals a self-assembling nanocage that to a significant degree helps shape basic human physiology from birth to death, and could one day lead to new treatment approaches to a number of diseases including diabetes and Alzheimer's disease. This new knowledge will allow further study of the structure's function in building and maintaining membranes required for exporting key molecules such as insulin, involved in the onset of diabetes, and beta amyloid, associated with Alzheimer's disease. TSRI Professor William E. Balch, Ph.D., led the study. One-third of the proteins encoded by the genome flow through this transport cage. These proteins ultimately control all aspects of cell structure, differentiation, signaling, and proliferation-and when defects occur during transport, the result may be any one of several serious disorders. Expanding our knowledge of this cage structure is fundamental to our understanding of the organization and function of the membrane architecture of every cell in the human body and eukaryotic cells in general. In some ways, our understanding the structure of the nanocage provides a similar level of insight to function in cell biology as the structure of DNA provided key insight into the genetic code.

The results show that the function of Sec13/31 is analogous to that of clathrin, another cellular protein that can also self-assemble in vitro to form transport cages. However, these are strikingly different from the Sec13/31 cage. Balch's discovery that the self-assembling properties of Sec13/31 produce a unique nanocage structure offers an unprecedented opportunity to study what are most likely novel biological mechanisms underlying cargo selection, concentration and transport of the proteins that pass through this cellular architecture. This may help point the way toward new therapeutic approaches to a variety of diseases. Type II diabetes, amyloidosis, cystic fibrosis, childhood emphysema, and even cancer are caused by protein folding/packaging defects in the ER that result in either a loss of activity or a protein build up in the cell. One focus of Balch's laboratory has been to understand how these folding defects affect normal protein function within the transport pathway. Through their structural knowledge of the nanocage, they hope to gain critical insight into the basis of several inherited transport diseases. With it, they can begin to delve more deeply into the basic functions of these cargo selection and trafficking pathways. From there, they might be able to develop small molecule chemical modulators to encourage export and stability of misfolded proteins which may lead to restoring normal cellular function in these diseases.

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Study Reveals Structural Dynamics Of Single Prion Molecules
Using a combination of novel technologies, scientists at The Scripps Research Institute and the Whitehead Institute for Biomedical Research have revealed for the first time a dynamic molecular portrait of individual unfolded yeast prions that form the compound amyloid, a fibrous protein aggregate associated with neurodegenerative diseases such as Alzheimer's disease and variant Creutzfeldt-Jacob disease—the human version of mad cow disease. The new findings offer significant insights into normal folding mechanisms as well as those that lead to abnormal amyloid fibril conversion. The new insights may lead to the discovery of novel therapeutic targets for neurodegenerative diseases. Intriguingly, certain prions and amyloids can play beneficial roles. The subject of the new study, Sup35, enables protein-based inheritance in yeast. When this prion protein misfolds, it converts into self-perpetuating amyloid fibrils, thus altering its function in an inheritable manner. The research team used a combination of advanced biophysical methods to investigate these processes.

By focusing on single unfolded prions, the scientists were able to define the dynamics of two distinct regions or domains that determine conversion dynamics. Ashok A. Deniz, Ph.D., a Scripps Research scientist, led the study. His research techniques can now be used to probe the structures of other amyloidogenic proteins. This could prove important in understanding the basic biology of amyloid formation, as well as in designing strategies against misfolding diseases. Interestingly, the new study revealed that yeast prion protein Sup35 lacks a specific, static structure in its native collapsed state. Instead, the compact protein fluctuates among several different structures before forming intermediate shapes during the amyloid assembly process. The intermediate stages of the process are critically important. No single native unfolded protein is capable of initiating the amyloid cascade because of this constant shape-shifting. To start the amyloid conversion process, it has to first convert to an intermediate species, consisting of multiple protein molecules. This insight may be important to finding potential new therapeutic targets for disease-causing amyloids.

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Aging And Neurodegeneration
Scripps Florida Assistant Professor Malcolm Leissring, Ph.D., and his colleagues study diseases of the nervous system that occur during aging and the fundamental mechanisms that regulate aging. Currently, they are examining a fascinating but poorly understood zinc-metalloprotease known as insulin-degrading enzyme ( IDE). IDE is responsible for degradation of insulin and amyloid β-protein, peptide substrates central to the pathogenesis of diabetes and Alzheimer's disease, respectively. They have shown that enhancing the proteolysis of amyloid β-protein by IDE or other proteases can completely prevent Alzheimer-type pathologic changes in a mouse model of Alzheimer's disease.

They are using techniques ranging from in vitro enzymatic assays to transgenic and gene-targeted rodent models to explore the normal biology and therapeutic potential of IDE and other proteases. In parallel, they are using high-throughput screening of compounds, solid-phase peptide synthesis, and medicinal chemistry to discover and rationally design pharmacologic modulators of IDE. These pharmacologic tools promise to deepen our understanding of IDE biology and could lead to novel therapeutic interventions for Alzheimer's disease or diabetes.

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A Tempting New Target For Attacking Alzheimer's At Its Earliest Stage
With the tsunami of Alzheimer's gathering speed—as many as 16 million Americans may be afflicted by 2050—new understanding of the disease is welcome for efforts to help slow, or even stop, the disaster headed our way. Now, a computer simulation study by a pair of Scripps Research Institute scientists has revealed a novel pH-dependent molecular mechanism for the early aggregation of β-amyloid peptides, something that may offer a tempting new target for attacking amyloid at its earliest stage, shutting off the disease at what many consider to be its source. The study opens the door to critical questions concerning pH-dependent amyloid aggregation, and may, ultimately, provide a means of arresting that process. Charles L. Brooks III, Ph.D., a Scripps Research professor in molecular biology, led the study. A great deal of disparate data concerning pH levels and amyloid aggregation has now been made clearer and connectable. The study, which was conducted by Brooks and Jana Khandogin, a Brooks lab alumnus who is now an assistant professor at the University of Oklahoma, strongly supports the current theory that pre-fibrilar species of β-amyloid peptide (A β) may be the culprit of Alzheimer's disease, and that a very specific pH level makes the initial development of this peptide species possible.

In Alzheimer's disease, it is hypothesized that small bits of β-amyloid peptide—called oligomers—form in endosomes (a membrane-bound compartment inside cells) and are then expelled into the extracellular fluid, where they may start to disrupt neuronal activity and develop into amyloid fibrils (clumps). Protein aggregation and fibril formation have also been implicated in at least 16 other diseases, including Parkinson's and Huntington's. In biological systems and cell compartments molecules are constantly bathed in various pH values. It seems obvious that changes in pH levels should have influence on conformational changes—and the functioning or misfunctioning of proteins like the β-amyloid peptides. To explore the impact of pH on biological processes like amyloid aggregation, Brooks and Khandogin used computer simulation techniques to focus on a pair of model peptides, A β (1-28) and A β (10-42). The scientists found that the folding landscape of the peptides was strongly modulated by pH—and that the most favorable aggregation environment was pH 6; basically the same as milk. That pH is like the Goldilocks equivalent of porridge. Not too hot, not too cold. At pH 6, the peptides adopt conformations that are very 'fibril-friendly'—that is, they're already poised to form larger sheet-based oligomers, the next step up the toxicity ladder. As a result, their theoretical findings substantiate the possibility that Aβ oligomers are formed first in endosomes.

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Scripps Research Scientists Find Protein May Protect Against Alzheimer's Disease
Scientists at The Scripps Research Institute report that a protein capable of producing what has been called "Alzheimer's of the heart" has been found to protect against development of Alzheimer's disease in the brain of rodent models. The scientists say the findings suggest that the protein, transthyretin (TTR), could represent a powerful natural defense against development of Alzheimer's disease in humans, a defense that diminishes as people grow older. If so, TTR-based therapy might help treat or prevent the disorder.

Professor Joel Buxbaum, M.D., of the Scripps Research Department of Molecular and Experimental Medicine, led the investigation that found genetic and biochemical evidence that a protein that makes tissue compromising amyloid deposits in one circumstance can be an amyloid inhibitor in another.

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Scripps Florida Scientists Find New Clue To Alzheimer's Disease Progression – Non-coding R.N.A. Could Become Target For Potential Diagnostic And Therapuetic Development
Scientists from Scripps Florida, a division of The Scripps Research Institute, have shown for the first time that a specialized form of RNA is directly linked to increased levels of amyloid plaque in the brains of Alzheimer's patients. The in vitro as well as in vivo studies show that a previously unknown molecule, BACE1-AS, regulates a critical mechanism associated with Alzheimer's disease, and may turn out to be key to the pathological progression of the disease. Claes Wahlestedt, M.D. Ph.D., a Scripps Florida professor, led the study. The study shows that a noncoding antisense form of RNA – an RNA that does not encode a protein– controls the expression of β-secretase-1 (BACE1), an enzyme critical to Alzheimer's disease progression. This noncoding antisense RNA, termed BACE1-AS, could be an attractive target for potential new diagnostic as well as therapeutic approaches.

The new study's findings show that when BACE1-AS (pronounced base) is exposed to stress, it stabilizes BACE1 messenger RNA, increasing expression of BACE1 and leading to higher levels of amyloid-β 1-42, the peptide believed to be the primary cause of Alzheimer's disease. Importantly, the levels of BACE1-AS were sharply elevated in brains from deceased individuals who had suffered from Alzheimer's disease. Wahlestedt and his colleagues showed that BACE1-AS could be a potential disease biomarker as well as drug target, well suited to mediate the balance between the essential physiological functions of BACE1 and its pathological malfunction in early Alzheimer's disease. In the study, Wahlestedt and his colleagues used a synthetic small interfering RNA (siRNA) – which can inhibit gene expression – to decrease BACE1-AS expression in animal models and reduce amyloid generation successfully. Those animal model experiments support the validity of a siRNA approach. Recent technological breakthroughs suggest that systemic administration of modified siRNAs, which cross the blood-brain barrier, could in fact target RNA transcripts there. Alternatively, proteins involved in BACE1-AS localization or turnover could also become targets for potential therapeutics.

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Scripps Research Scientists Uncover New Mechanism Closely Linked to Neurodegeneration and Alzheimer's
Scientists from The Scripps Research Institute have uncovered a novel mechanism that may play a significant role in the development of Alzheimer's disease and a host of other neurodegenerative conditions. The discovery of this mechanism points towards potential new targets that could lead to treatments to enhance neuron survival. The new study sheds light on the formation of large rod-shaped inclusion bodies that contribute to neurodegenerative injury and dysfunction. These rod-shaped assemblies, which are made up of the important protein actin (necessary for cell movement and division) and its key regulatory component cofilin, appear in abundance in animal models of neurodegeneration. These inclusions are especially abundant near amyloid deposits and neurofibrillary tangles in Alzheimer's disease.

Actin/cofilin rods are abundant in brains of neurodegenerative disease patients, particularly Alzheimer's patients, and have long been suspected of playing a role in the progression of the underlying disease. Scripps Research Professor Gary Bokoch, Ph.D., conducted the study with Scripps Research postdoctoral fellow Timothy Huang, Ph.D., and colleagues. Until their study, no one really knew how these rods were formed. The study uncovered a mechanism for the formation of these rods during periods of energy stress that points to chronophin as an important new target for interrupting the process of neurodegeneration. It's a critical component of this pathway. The brain, which represents just two percent of the body mass, uses 20 percent of the body's energy, making neurons highly susceptible to fluctuations in energy production from vascular or ischemic disturbances. The new study shows that chronophin, a cofilin-activating phosphatase, normally interacts with heat shock protein-90 (HSP90), a common molecular chaperone, to limit cofilin activation and consequent formation of cofilin/actin rods. When stress and/or cell damage depletes neurons of the nucleotide ATP, an important source of energy for the neuron, then chronophin is released from Hsp90 to become active, thus triggering the cofilin/actin rod-forming mechanism. The Hsp90-chronophin complex thus acts as an endogenous "biosensor" to detect energy depletion and invoke this (initially) protective response.

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