Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Scientists Identify ‘Clean-Up’ Snafu That Kills Brain Cells in Parkinson’s Disease
Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The study, which published online in the journal Nature Neuroscience, could also open up treatment possibilities for both familial Parkinson’s and the more common form of Parkinson’s that is not inherited.
"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson’s patients," said study leader Ana Maria Cuervo, M.D., Ph.D., professor of developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases at Einstein.
The name for the disrupted disposal process is chaperone-mediated autophagy (the word “autophagy” literally means “self-eating”). It involves specialized molecules that “guide” old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.
"We showed that when LRRK2 inhibits chaperone-mediated autophagy,
alpha-synuclein doesn’t get broken down and instead accumulates to toxic levels in nerve cells,” said Dr. Cuervo.
The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.
"We’re now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease," said Dr. Cuervo. "We’ve started to analyze some chemical compounds that look very promising."
Dr. Cuervo hopes that such treatments could help patients with familial as well as nonfamilial Parkinson’s - the predominant form of the disease that also involves the buildup of alpha-synuclein.
Dr. Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as cancer and Huntington’s disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr. Cuervo is co-director of Einstein’s Institute of Aging Research.
(Image: Shutterstock)
Misplaced molecules: New insights into the causes of dementia
A shortage of a protein called TDP-43 caused muscle wasting and stunted nerve cells. This finding supports the idea that malfunction of this protein plays a decisive role in ALS and FTD. The study is published in the “Proceedings of the National Academy of Sciences of the USA" (PNAS).
ALS is an incurable neurological disease which manifests as rapidly progressing muscle wasting. Both limbs and respiratory muscles are affected. This leads to impaired mobility and breathing problems. Patients commonly die within a few years after the symptoms emerged. In rare cases, of which the British physicist Stephen Hawking is the most notable, patients can live with the disease for a long time. In Germany estimates show over 150,000 patients suffering from ALS – an average of 1 in 500 people.
Proteins gone astray
Over the last few years, there has been increasing evidence that ALS and FTD – a form of dementia associated with changes in personality and social behaviour – may have similar or even the same origins. The symptoms overlap and common factors have also been found at the microscopic level. In many cases, particles accumulate and form clumps in the patient’s nerve cells: this applies particularly to the TDP-43 protein.
"Normally, this protein is located in the cell nucleus and is involved in processing genetic information," explains molecular biologist Dr. Bettina Schmid, who works at the DZNE Munich site and at LMU. "However, in cases of disease, TDP-43 accumulates outside the nucleus forming aggregates." Schmid explains that it is not yet clear whether these clumps are harmful. "However, the protein’s normal function is clearly disrupted. It no longer reaches the nucleus to perform its actual task. There seems to be a relationship between this malfunction and the disease."
Studies on zebrafish
However, until now little was known about the function of TDP-43. What are the consequences when this protein becomes non-functional? In order to answer this question, the team led by Bettina Schmid cooperated with the research group of Prof. Christian Haass to investigate the larvae of specially bred zebrafish. Their genetic code had been modified in such a way that no TDP-43 was produced in the organism of the fish. The result: the young fish showed massive muscle wasting and died a few days after hatching. Moreover, the extensions of the nerve cells which control the muscles were abnormal.
"To some extent, these are symptoms typical of ALS and FTD. Therefore, a loss of function of TDP-43 does seem to play a critical role in the disease," says Haass, Site Speaker of the DZNE Munich Site and chair of Metabolic Biochemistry at LMU.
The study revealed one more finding which surprised the researchers: the blood flow of the fish was massively disturbed. “It is well known that circulatory disorders play a part in other forms of dementia, notably in the case of Alzheimer’s,” says Haass. “We now want to investigate whether such problems with blood flow may be a general problem of neurodegenerative diseases and whether such problems occur particularly in patients with ALS and FTD.”
(Source: eurekalert.org)
Research reveals Huntington’s hope
Researchers in Scotland and Germany have discovered a molecular mechanism that shows promise for developing a cure for Huntington’s Disease (HD).
Scientists from the University of Dundee, the German Center for Neurodegenerative Diseases (DZNE) in Bonn, the Max-Planck Institute for Molecular Genetics in Berlin and the Johannes Gutenberg-Universität Mainz have found a mechanism that specifically stirs and induces the synthesis of disease-making protein in HD patients.
Their data lead to the conclusion that a selective overproduction of aberrant Huntington protein in patients is a key step in the establishment of the disease, which affects 1 in 10,000 people in Western countries and is so far incurable.
"This is a very promising strategy to develop a small molecule drug therapy that is able to inhibit the production of disease-making protein," said Professor Susann Schweiger of the University of Dundee and Johannes Gutenberg-Universität Mainz.
"Theoretically, if you don’t have the disease-making protein then you don’t have the disease. Obviously we still have work to do to develop a drug to target these mechanisms and inhibit the production of this protein but we think this research is attractive to drug discovery and ongoing work in this area is being carried out."
The gene responsible for causing Huntington’s Disease was first identified in 1993, leading to hopes that a specific therapy for HD would soon be on the market. However, cell biology and brain pathology of HD showed it to be more complicated than originally anticipated and only symptomatic treatments to slightly relieve the distress of single components of the disease are currently available.
The new discovery once again raises hopes that a curative therapy can be established. The scientists found that it was mainly three proteins - the mammalian target of rapamycin (mTOR), protein phosphatase 2A (PP2A) and Midline 1 (MID1) - that specifically drive the production of disease-making protein in HD patients.
As a result, more and more aberrant protein is produced with time, which leads to a protein overload in the cell. By interfering with the function of the three proteins it is possible to disrupt this circle and prevent the synthesis of aberrant protein in HD patients.
The Dundee-Germany research is published in the latest edition of the Nature Communications journal.
Discovery on animal memory opens doors to research on memory impairment diseases
If you ask a rat whether it knows how it came to acquire a certain coveted piece of chocolate, Indiana University neuroscientists conclude, the answer is a resounding, “Yes.” A study newly published in the journal Current Biology offers the first evidence of source memory in a nonhuman animal.
The findings have “fascinating implications,” said principal investigator Jonathon Crystal, both in evolutionary terms and for future research into the biological underpinnings of memory, as well as the treatment of diseases marked by memory failure such as Alzheimer’s, Parkinson’s and Huntington’s, or disorders such as schizophrenia, PTSD and depression.
The study further opens up the possibility of creating animal models of memory disorders.
"Researchers can now study in animals what was once thought an exclusively human domain," said Crystal, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences. "If you can export types of behaviors such as source memory failures to transgenic animal models, you have the ability to produce preclinical models for the treatment of diseases such as Alzheimer’s."
Of the various forms of memory identified by scientists, some have long been considered distinctively human. Among these is source memory. When someone retells a joke to the person who told it to him, it is an everyday example of source memory failure. The person telling the joke forgot the source of the information — how he acquired it — though not the information he was told. People combine source information to construct memories of discrete events and to distinguish one event or episode from another.
Nonhuman animals, by contrast, have been thought to have limited forms of memory, acquired through conditioning and repetition, habits rather than conscious memories. The kind of memory failures most devastating to those directly affected by Alzheimer’s have typically been considered beyond the scope of nonhuman minds.
The study owes much to another quality these rodents share with humans: They love chocolate. “There’s no amount of chocolate you can give to a rat which will stop it from eating more chocolate,” Crystal said.
A three molecule complex may be a target for treating Huntington’s disease, a genetic disorder affecting the brain. This finding by an international research team including scientists from the German Center for Neurodegenerative Diseases (DZNE) in Bonn and the University of Mainz was published in the online journal “Nature Communications”. The report states that the so-called MID1 complex controls the production of a protein which damages nerve cells.
The long DNA sequences in Huntington’s disease lead to changes in a certain protein called “Huntingtin”. The DNA is like an archive of blueprints for proteins. Errors in the DNA therefore result in defective proteins. “Huntingtin is essential for the organism’s survival. It is a multi-talent which is important for many processes,” emphasises Krauss. “If the protein is defective, brain cells may die.“
In the spotlight: protein synthesis
In the current study, the scientists around Sybille Krauss and the Mainz-based human geneticist Susann Schweiger took a closer look at a critical stage of protein production – translation. At this step, a copy of the DNA, the so-called messenger RNA, is processed by the cell’s protein factories. In patients with Huntington’s disease, the messenger RNA contains an unusually high number of consecutive CAG sequences – CAG representing the building plan for the amino acid glutamine.
These repetitive sequences have a direct consequence: more glutamine than normal is built into Huntingtin, which is therefore defective. Sybille Krauss and her colleagues have now identified a group of three molecules, which regulate the production of this protein. “We were able to show that this complex binds to the messenger RNA and controls the synthesis of defective Huntingtin,” says Krauss. When the scientists reduced the concentration of this so-called MID1 complex in the cell, production of the defective protein declined.
“If we could find a way of influencing this complex, for example with pharmaceuticals, it is quite possible that we could directly affect the production of defective Huntingtin. This kind of treatment would not just treat the symptoms but also the causes of Huntington’s disease,” says Krauss.
Background:Three molecules come together
The complex consists of MID1, from which it gets its name, and the proteins PP2Ac and S6K. “Every single one of these proteins is known to be important for translation. We have discovered that in the specific case of Huntington’s disease, they together bind to the CAG sequences. This was previously unknown. We also found that binding increases with repeat lengths,” says Krauss. “In sequences of normal length, we found only weak binding or none at all.”
The Bonn-based molecular biologist and her colleagues investigated the effect of the MID1 complex and the interaction between its components in a series of elaborate laboratory experiments. “This project took several years of research work,” says Krauss. Along with biochemical procedures, the scientists used cell cultures and analysed proteins from the brains of mice. The mice’s genetic code had been modified in such a way that it contained elongated CAG-repeats as it is typical for Huntington’s disease.
From previous studies it was already known that the protein MID1 tends to bind messenger RNAs. The scientists were now able to show that MID1 also attaches to messenger RNAs with excessively long CAG sequences. Furthermore, experiments showed that PP2Ac and S6K also bound the RNA in the presence of MID1. However, if the MID1 was depleted, this binding did not occur. “From this, we can conclude that these three proteins form a molecular complex, which binds to the RNA. MID1 is a key component. It actually seems to keep together its binding partners,” Krauss comments on the results of the experiments.
Complex controls protein production
The researchers were also able to prove that the MID1 complex controls the translation of RNA with excessively long CAG sequences. For this, they investigated various cell cultures. The cells produced either normal Huntingtin or – due to excessively long sequences in their DNA – a defective version of this protein. The scientists reduced the occurrence of MID1 inside the cells using a procedure known as “knock-down”. The elimination of this protein, which is a major part of the MID1 complex, had direct consequences: the production of defective Huntingtin declined. “However, it did not affect the production of normal Huntingtin,” emphazises Krauss. “This further proves that the MID1 complex specifically targets RNAs with excessively long CAG sequences.”
Highly specific
The Bonn-based molecular biologist sees this specific influence as a chance to treat Huntington’s disease: “The MID1 complex is a promising target for therapy. It indicates a possibility to suppress the production of defective Huntingtin only, while not affecting the production of normal Huntingtin. This is of particular significance, because the normal protein is also being produced in the patients’ bodies and it is important for the organism.”
A suitable active substance has yet to be found, says Krauss. However, the next developments are in sight: “We now want to test potential substances in the laboratory,” she says.
Scientists find genes linked to human neurological disorders in sea lamprey genome
Scientists at the Marine Biological Laboratory (MBL) have identified several genes linked to human neurological disorders, including Alzheimer’s disease, Parkinson’s disease and spinal cord injury, in the sea lamprey, a vertebrate fish whose whole-genome sequence is reported this week in the journal Nature Genetics.
"This means that we can use the sea lamprey as a powerful model to drive forward our molecular understanding of human neurodegenerative disease and neurological disorders," says Jennifer Morgan of the MBL’s Eugene Bell Center for Regenerative Biology and Tissue Engineering. The ultimate goals are to determine what goes wrong with neurons after injury and during disease, and to determine how to correct these deficits in order to restore normal nervous system functions.
Unlike humans, the lamprey has an extraordinary capacity to regenerate its nervous system. If a lamprey’s spinal cord is severed, it can regenerate the damaged nerve cells and be swimming again in 10-12 weeks.
Morgan and her collaborators at MBL, Ona Bloom and Joseph Buxbaum, have been studying the lamprey’s recovery from spinal cord injury since 2009. The lamprey has large, identified neurons in its brain and spinal cord, making it an excellent model to study regeneration at the single cell-level. Now, the lamprey’s genomic information gives them a whole new “toolkit” for understanding its regenerative mechanisms, and for comparing aspects of its physiology, such as inflammation response, to that of humans.
The lamprey genome project was accomplished by a consortium of 59 researchers led by Weiming Li of Michigan State University and Jeramiah Smith of the University of Kentucky. The MBL scientists’ contribution focused on neural aspects of the genome, including one of the project’s most intriguing findings.
Lampreys, in contrast to humans, don’t have myelin, an insulating sheath around neurons that allows faster conduction of nerve impulses. Yet the consortium found genes expressed in the lamprey that are normally expressed in myelin. In humans, myelin-associated molecules inhibit nerves from regenerating if damaged. “A lot of the focus of the spinal cord injury field is on neutralizing those inhibitory molecules,” Morgan says.
"So there is an interesting conundrum," Morgan says. "What are these myelin-associated genes doing in an animal that doesn’t have myelin, and yet is good at regeneration? It opens up a new and interesting set of questions, " she says. Addressing them could bring insight to why humans lost the capacity for neural regeneration long ago, and how this might be restored.
At present, Morgan and her collaborators are focused on analyzing which genes are expressed and when, after spinal cord injury and regeneration. The whole-genome sequence gives them an invaluable reference for their work.
Ability of brain to protect itself from damage revealed
(Image: Matthias Kulka / Corbis)
The origin of an innate ability the brain has to protect itself from damage that occurs in stroke has been explained for the first time.
The Oxford University researchers hope that harnessing this inbuilt biological mechanism, identified in rats, could help in treating stroke and preventing other neurodegenerative diseases in the future.
'We have shown for the first time that the brain has mechanisms that it can use to protect itself and keep brain cells alive,' says Professor Alastair Buchan, Head of the Medical Sciences Division and Dean of the Medical School at Oxford University, who led the work.
The researchers report their findings in the journal Nature Medicine and were funded by the UK Medical Research Council and National Institute for Health Research.
Stroke is the third most common cause of death in the UK. Every year around 150,000 people in the UK have a stroke.
It occurs when the blood supply to part of the brain is cut off. When this happens, brain cells are deprived of the oxygen and nutrients they need to function properly, and they begin to die.
'Time is brain, and the clock has started immediately after the onset of a stroke. Cells will start to die somewhere from minutes to at most 1 or 2 hours after the stroke,' says Professor Buchan.
This explains why treatment for stroke is so dependent on speed. The faster someone can reach hospital, be scanned and have drugs administered to dissolve any blood clot and get the blood flow re-started, the less damage to brain cells there will be.
It has also motivated a so-far unsuccessful search for ‘neuroprotectants’: drugs that can buy time and help the brain cells, or neurons, cope with damage and recover afterwards.
The Oxford University research group have now identified the first example of the brain having its own built-in form of neuroprotection, so-called ‘endogenous neuroprotection’.
They did this by going back to an observation first made over 85 years ago. It has been known since 1926 that neurons in one area of the hippocampus, the part of the brain that controls memory, are able to survive being starved of oxygen, while others in a different area of the hippocampus die. But what protected that one set of cells from damage had remained a puzzle until now.
'Previous studies have focused on understanding how cells die after being depleted of oxygen and glucose. We considered a more direct approach by investigating the endogenous mechanisms that have evolved to make these cells in the hippocampus resistant,' explains first author Dr Michalis Papadakis, Scientific Director of the Laboratory of Cerebral Ischaemia at Oxford University.
Working in rats, the researchers found that production of a specific protein called hamartin allowed the cells to survive being starved of oxygen and glucose, as would happen after a stroke.
They showed that the neurons die in the other part of the hippocampus because of a lack of the hamartin response.
The team was then able to show that stimulating production of hamartin offered greater protection for the neurons.
Professor Buchan says: ‘This is causally related to cell survival. If we block hamartin, the neurons die when blood flow is stopped. If we put hamartin back, the cells survive once more.’
Finally, the researchers were able to identify the biological pathway through which hamartin acts to enable the nerve cells to cope with damage when starved of energy and oxygen.
The group points out that knowing the natural biological mechanism that leads to neuroprotection opens up the possibility of developing drugs that mimic hamartin’s effect.
Professor Buchan says: ‘There is a great deal of work ahead if this is to be translated into the clinic, but we now have a neuroprotective strategy for the first time. Our next steps will be to see if we can find small molecule drug candidates that mimic what hamartin does and keep brain cells alive.
'While we are focussing on stroke, neuroprotective drugs may also be of interest in other conditions that see early death of brain cells including Alzheimer's and motor neurone disease,' he suggests.
(Source: eurekalert.org)
Scientists from the University of Southampton have identified the molecular system that contributes to the harmful inflammatory reaction in the brain during neurodegenerative diseases.
An important aspect of chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s or prion disease, is the generation of an innate inflammatory reaction within the brain.
Results from the study open new avenues for the regulation of the inflammatory reaction and provide new insights into the understanding of the biology of microglial cells, which play a leading role in the development and maintenance of this reaction.
Dr Diego Gomez-Nicola, from the CNS Inflammation group at the University of Southampton and lead author of the paper, says: “The understanding of microglial biology during neurodegenerative diseases is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease.
“The future potential outcomes of this line of research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with these diseases.”
Microglial cells multiply during different neurodegenerative conditions, although little is known about to what extent this accounts for the expansion of the microglial population during the development of the disease or how it is regulated.
Writing in The Journal of Neuroscience, scientists from the University of Southampton describe how they used a laboratory model of neurodegeneration (murine prion disease), to understand the brain’s response to microglial proliferation and dissected the molecules regulating this process. They found that signalling through a receptor called CSF1R is a key for the expansion of the microglial population and therefore drugs could target this.
Dr Diego Gomez-Nicola adds: “We have been able to identify that this molecular system is active in human Alzheimer’s disease and variant Creutzfeldt–Jakob disease, pointing to this mechanism being universal for controlling microglial proliferation during neurodegeneration. By means of targeting CSF1R with selective inhibitors we have been able to delay the clinical symptoms of experimental prion disease, also preventing the loss of neurons.”
Engineering control theory helps create dynamic brain models
Models of the human brain, patterned on engineering control theory, may some day help researchers control such neurological diseases as epilepsy, Parkinson’s and migraines, according to a Penn State researcher who is using mathematical models of neuron networks from which more complex brain models emerge.
"The dual concepts of observability and controlability have been considered one of the most important developments in mathematics of the 20th century," said Steven J. Schiff, the Brush Chair Professor of Engineering and director of the Penn State Center for Neural Engineering. "Observability and controlability theorems essentially state that if you can observe and reconstruct a system’s variables, you may be able to optimally control it. Incredibly, these theoretical concepts have been largely absent in the observation and control of complex biological systems."
Those engineering concepts were originally designed for simple linear phenomena, but were later revised to apply to non-linear systems. Such things as robotic navigation, automated aircraft landings, climate models and the human brain all require non-linear models and methods.
"If you want to observe anything that is at all complicated — having more than one part — in nature, you typically only observe one of the parts or a small subset of the many parts," said Schiff, who is also professor of neurosurgery, engineering science and mechanics, and physics, and a faculty member of the Huck Institutes of the Life Sciences. "The best way of doing that is make a model. Not a replica, but a mathematical representation that uses strategies to reconstruct from measurements of one part to the many that we cannot observe."
This type of model-based observability makes it possible today to create weather predictions of unprecedented accuracy and to automatically land an airliner without pilot intervention.
"Brains are much harder than the weather," said Schiff. "In comparison, the weather is a breeze."
There are seven equations that govern weather, but the number of equations for the brain is uncountable, according to Schiff. One of the problems with modeling the brain is that neural networks in the brain are not connected from neighbor to neighbor. Too many pathways exist.
"We make and we have been making models of the brain’s networks for 60 years," Schiff said at the recent annual meeting of the American Association for the Advancement of Science in Boston. “We do that for small pieces of the brain. How retina takes in an image and how the brain decodes that image, or how we generate simple movements are examples of how we try now to embody the equations of motion of those limited pieces. But we never used the control engineer’s trick of fusing those models with our measurements from the brain. This is the key — a good model will synchronize with the system it is coupled to.”
(Image: Photograph by Anne Keiser, National Geographic; model by Yeorgos Lampathakis)
Obama Seeking to Boost Study of Human Brain
The Obama administration is planning a decade-long scientific effort to examine the workings of the human brain and build a comprehensive map of its activity, seeking to do for the brain what the Human Genome Project did for .
The project, which the administration has been looking to unveil as early as March, will include federal agencies, private foundations and teams of neuroscientists and nanoscientists in a concerted effort to advance the knowledge of the brain’s billions of neurons and gain greater insights into perception, actions and, ultimately, consciousness.
Scientists with the highest hopes for the project also see it as a way to develop the technology essential to understanding diseases like and , as well as to find new therapies for a variety of mental illnesses.
Moreover, the project holds the potential of paving the way for advances in artificial intelligence.
The project, which could ultimately cost billions of dollars, is expected to be part of the president’s budget proposal next month. And, four scientists and representatives of research institutions said they had participated in planning for what is being called the Brain Activity Map project.
The details are not final, and it is not clear how much federal money would be proposed or approved for the project in a time of fiscal constraint or how far the research would be able to get without significant federal financing.
In his State of the Union address, cited brain research as an example of how the government should “invest in the best ideas.”
“Every dollar we invested to map the human genome returned $140 to our economy — every dollar,” he said. “Today our scientists are mapping the human brain to unlock the answers to Alzheimer’s. They’re developing drugs to regenerate damaged organs, devising new materials to make batteries 10 times more powerful. Now is not the time to gut these job-creating investments in science and innovation.”