#Researchers Discover How a Protein Crucial to Learning and Memory Works Researchers at Johns Hopkins have found out how a protein crucial to learning works:
by removing a biochemical lampthat prevents connections between nerve cells in the brain from growing stronger.
The finding moves neuroscientists a step closer to figuring out how learning and memory work,
and how problems with them can arise. A report on the discovery appears Jan 7 in the journal Neuron.
says Rick Huganir, Ph d.,director of the Solomon H. Snyder Department of Neuroscience at the Johns hopkins university School of medicine.
which is needed for learning. An influx of calcium into the synapse activates Camkii, which in turn unhooks Syngap from the cellsscaffolding
Studies at other institutions have identified mutations in the gene for Syngap associated with autism and intellectual disability.
To see how these mutations affect the protein function the Johns Hopkins research team altered their lab-grown cells
so that they had genes with one of three of these mutations. All three of the disability-associated mutations showed similar effects:
Compared to normal neurons, there was less Syngap in synapses when they were at rest, but activating Camkii did not noticeably change anything. his gives us a much clearer idea of how some Syngap mutations cause problems in the brain,
Huganir says. The findings may one day lead to drugs or other interventions that would lessen the effects of the mutations,
he says. Other authors on the paper are Menglong Zeng and Mingjie Zhang, both of Hong kong University of Science and Technology c
#Researchers Redefine Role of Brain's'Hunger Circuit'Using techniques developed only over the past few years,
But the new work shows that the Agrp-POMC circuit responds within seconds to the mere presence of food,
assistant professor of physiology at UCSF. hese findings really change our view of what this region of the brain is doing.
which collectively occupy an area smaller than a millimeter in the mouse brain, are organized functionally in a seesaw-like fashion:
and POMC neurons have laid the foundation of the dominant model of how the hunger circuit works.
a graduate student in Knight lab, was expecting to build on the prevailing model of the hunger circuit
when he began experiments using newly developed fiber optic devices that allowed him to record Agrp-POMC activity in real time as mice were given food after a period of fasting. o one had recorded actually the activity of these neurons in a behaving mouse,
if we gave a hungry mouse some food, then slowly, over many minutes, it would become satiated
If you simply give food to the mouse, almost immediately the neurons reversed their activation state.
This happens when the mouse first sees and smells the food, before they even take a bite.
The fact that more accessible and more palatable, energy-rich foods engage POMC neurons and shut down Agrp activity more strongly suggests that the circuit also has nticipatoryaspects, by
likewise, since energy-dense foods alleviate hunger for longer periods, discovery of these foods should more strongly tamp down the hunger circuit
We might be manipulating the decision to go to the grocery store, not necessarily the decision to take the next bite of food.
and graduate student Tzu-Wei Kuo. The research was supported by the New york Stem Cell Foundation, the Rita Allen Foundation
Biomedical Research, the UCSF Diabetes Center Obesity Pilot program, and the National institutes of health b
#New ALS Gene and Signaling Pathways Identified Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS),
or Lou Gehrig disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement
and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2, 874 ALS patients and 6,
inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components.
The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical center (CUMC), Biogen idec,
and Hudsonalpha Institute for Biotechnology, was published today in the online edition of Science. he identification of TBK1 is exciting for understanding ALS pathogenesis,
especially since the inflammatory and autophagy pathways have been implicated previously in the disease, said Lucie Bruijn, Phd,
Chief Scientist for The ALS Association. he fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease.
but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts,
said study co-leader David B. Goldstein, Phd, professor of genetics and development and director of the new Institute for Genomic medicine at CUMC.
LS is an incredibly diverse disease, caused by dozens of different genetic mutations, which wee only beginning to discover.
The more of these mutations we identify the better we can deciphernd influencehe pathways that lead to disease.
The other co-leaders of the study are Richard M. Myers, Phd, president and scientific director of Hudsonalpha,
and Tim Harris, Phd, DSC, Senior vice president, Technology and Translational Sciences, Biogen idec. hese findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential
points of intervention. We are following up by looking at the function of this pathway
focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease.
This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."
"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen idec.
Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University,
as well as our teams here at Hudsonalpha, said Dr. Myers. love this research model because it doesn happen very frequently,
The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information
Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS,
TBK1 mutations appeared in about 1 percent of the ALS patients large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein.
may actually be a major player in the disease. emarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene,
Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS,
said Dr. Goldstein. hus there seems to be no question that aberrations in the pathways that require TBK1
and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates.
Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival. his is a great example of the potential of precision medicine,
said Tom Maniatis, Phd, the Isidore S. Edelman Professor, chair of biochemistry and molecular biophysics,
and coauthor on the paper. Dr. Maniatis is also a member of the Zuckerman Mind Brain Behavior Institute
and director of Columbia university-wide precision medicine initiative. t now seems clear that future ALS treatments will not be equally effective for all patients because of the disease genetic diversity.
as candidate therapies become available, we hope to be able to use the genetic data from each ALS patient to direct that person to the most appropriate clinical trials and,
ultimately, use the data to prescribe treatment. d
#New Brain Mapping Reveals Unknown Cell Types Using a process known as single cell sequencing, scientists at Karolinska Institutet have produced a detailed map of cortical cell types and the genes active within them.
The study, which is published in the journal cience marks the first time this method of analysis has been used on such a large scale on such complex tissue.
you could say that previous methods were like running the fruit through a blender and seeing
senior researcher at the Department of Medical Biochemistry and Biophysics. ut in recent years wee developed much more sensitive methods of analysis that allow us to see which genes are active in individual cells.
protect against infection and supply nerve cells with nutrients. With the help of this detailed map, the scientists were able to identify hitherto unknown cell types,
The new knowledge the project has generated can shed more light on diseases that affect the myelin
such as multiple sclerosis (MS). e could also confirm previous findings, such as that the pyramidal cells of the cerebral cortex are organised functionally in layers,
This gives science a new tool for studying these cell types in disease models and helps us to understand better how brain cell respond to disease and injury.
There are estimated to be 100 million cells in a mouse brain and 65 billion in a human brain.
Nerve cells are approximately 20 micrometres in diameter, glial cells about 10 micrometres. A micrometre is equivalent to a thousandth of a millimetre.
The study was carried out by Sten Linnarsson and Jens Hjerling-Leffler research groups at the department of medical biochemistry and biophysics, in particular by Amit Zeisel and Ana Muños Manchado.
It also involved researchers from Karolinska Institutet Department of Oncology-Pathology, and Uppsala University. The study was financed with grants from several bodies,
including the European Research Council, the Swedish Research Council, the Swedish Cancer Society, the EU Seventh Framework Programme, the Swedish Society of Medicine, the Swedish Brain Fund, Karolinska Institutet strategic programme for neuroscience (Stratneuro), the Human Frontier Science Program
, the Åke Wiberg Foundation and the Clas Groschinsky Memorial Fund s
#Molecular Inhibitor Breaks Cycle That Leads to Alzheimer's A molecular chaperone has been found to inhibit a key stage in the development of Alzheimer disease and break the toxic chain reaction that leads to the death of brain cells, a new study shows.
The research provides an effective basis for searching for candidate molecules that could be used to treat the condition.
A molecule that can block the progress of Alzheimer disease at a crucial stage in its development has been identified by researchers in a new study,
raising the prospect that more such molecules may now be found. The report shows that a molecular chaperone
breaking the cycle of events that scientists believe leads to the disease. Specifically, the molecule, called Brichos, sticks to threads made up of malfunctioning proteins, called amyloid fibrils,
which are the hallmark of the disease. By doing so, it stops these threads from coming into contact with other proteins,
thereby helping to avoid the formation of highly toxic clusters that enable the condition to proliferate in the brain.
This step where fibrils made up of malfunctioning proteins assist in the formation of toxic clusters is considered to be one of the most critical stages in the development of Alzheimer in sufferers.
scientists have moved closer to identifying a substance that could eventually be used to treat the disease.
The research was carried out by an international team comprising academics from the Department of chemistry at the University of Cambridge, the Karolinska Institute in Stockholm, Lund University, the Swedish University of Agricultural sciences,
and Tallinn University. Their findings are reported in the journal Nature Structural & Molecular biology. Dr Samuel Cohen
a Research Fellow at St john College, Cambridge, and a lead author of the report, said:
great deal of work in this field has gone into understanding which microscopic processes are important in the development of Alzheimer disease;
now we are now starting to reap the rewards of this hard work. Our study shows, for the first time, one of these critical processes being inhibited specifically,
so we can prevent the toxic effects of protein aggregation that are associated with this terrible condition.
Alzheimer disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape
however a second critical step in the disease development. After amyloid fibrils first form from misfolded proteins, they help other proteins
These oligomers are highly toxic to nerve cells and are thought now to be responsible for the devastating effects of Alzheimer disease.
This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers
and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided,
which is a much slower and far less devastating process. By studying the molecular processes by
which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only
what happens during the progression of Alzheimer disease, but also what might happen if one stage in the process was switched somehow off. e had reached a stage where we knew what the data should look like
if we inhibited any given step in the process, including secondary nucleation, Cohen said. orking closely with our collaborators in Sweden who had developed groundbreaking experimental methods to monitor the process we were able to identify a molecule that produced exactly the results that we were hoping to see in experiments.
The results indicated that the molecule, Brichos, effectively inhibits secondary nucleation. Typically, Brichos functions as a olecular chaperonein humans;
it binds itself to catalytic sites on its surface. This essentially forms a coating that prevents the fibrils from assisting other proteins in misfolding
and nucleating into toxic oligomers. The research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer disease.
Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly.
When this happened in the presence of the molecular chaperone however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue,
confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer disease.
By modelling what might happen if secondary nucleation is switched off and then finding a molecule that performs that function,
if these can be used as the starting point for developing a future therapy. e
#Tau Associated MAPT Gene Increases Risk for Alzheimer's disease A international team of scientists, led by researchers at the University of California,
San diego School of medicine, has identified the microtubule associated-protein protein tau (MAPT) gene as increasing the risk for developing Alzheimer disease (AD).
The MAPT gene encodes the tau protein, which is involved with a number of neurodegenerative disorders, including Parkinson disease (PD) and AD.
These findings provide novel insight into Alzheimer neurodegeneration, possibly opening the door for improved clinical diagnosis and treatment.
The findings are published in the February 18 online issue of Molecular Psychiatry. Alzheimer disease, which afflicts an estimated 5 million Americans,
is characterized typically by progressive decline in cognitive skills, such as memory and language and behavioral changes.
While some recent AD genome-wide association studies (GWAS), which search the entire human genome for small variations,
have suggested that MAPT is associated with increased risk for AD, other studies have found no association.
In comparison, a number of studies have found a strong association between MAPT and other neurodegenerative disorders,
such as PD. hough a tremendous amount of work has been conducted showing the involvement of the tau protein in Alzheimer disease,
the role of the tau-associated MAPT gene is said still unclear Rahul S. Desikan, MD,
Phd, research fellow and radiology resident at the UC San diego School of medicine and the study first author.
This is a microscopic image of plaques and tangles associated with Alzheimer's. Microscopic image depicting plaques and tangles characteristic of Alzheimer disease.
Image credit: Tom Deerinck, NCMIR, UC San diego. In the new Molecular Psychiatry paper, conducted with collaborators across the country and world,
Desikan and colleagues narrowed their search. Rather than looking at all possible loci (specific gene locations),
the authors only focused on loci associated with PD and assessed whether these loci were associated also with AD,
thus increasing their statistical power for AD gene discovery. By using this approach, they found that carriers of the deleterious MAPT allele (an alternative form of the gene) are increased at risk for developing AD
and more likely to experience increased brain atrophy than non-carriers. his study demonstrates that tau deposits in the brains of Alzheimer disease subjects are not just a consequence of the disease,
and progression of the disease, said Gerard Schellenberg, Phd, professor of pathology and laboratory medicine at the University of Pennsylvania,
principal investigator of the Alzheimer Disease Genetics Consortium and a study co-author. n important aspect was the collaborative nature of this work.
Thanks to our collaborators from the Consortium, the International Parkinson Disease Genetics Consortium, the Genetic and Environmental Risk in Alzheimer Disease, the Cohorts for Heart and Aging research in Genomic Epidemiology, decode Genetics and the Demgene cohort,
professor of biological psychiatry at the University of Oslo and a senior co-author. Sudha Seshadri, MD, professor of neurology at the Boston University School of medicine, the principal investigator of the Neurology Working group within the Cohorts for Heart and Aging research in Genomic Epidemiology consortium and a study co-author added:
lthough it has been known since Alois Alzheimer time that both plaques (with amyloid) and tangles (of tau) are key features of Alzheimer pathology,
attempts to prevent or slow down clinical disease progression have focused on the amyloid pathway. Until this year no one had shown convincingly that the MAPT (tau) gene altered the risk of AD and this,
combined with the greater ease of imaging amyloid in life, lead some researchers to postulate that tau changes were secondary to amyloid changes.
The recent association of genetic variation in the MAPT gene with AD risk and the emerging availability of tau imaging are now leading to a recognition that perhaps tau changes are key in the pathophysiologic pathway of AD
These findings underscore the importance of using a multi-modal and multi-disciplinary approach to evaluating Alzheimer neurodegeneration. hese findings suggest that the combination of genetic,
molecular and neuroimaging measures may be additionally helpful for detecting and quantifying the biochemical effects of therapeutic interventions,
said Anders M. Dale, Phd, professor of neurosciences and radiology and director of the Center for Translational Imaging and Precision Medicine at UC San diego and the study senior author e
#What Autism Can Teach Us About Brain Cancer Both disorders involve faults in the same protein.
Applying lessons learned from autism to brain cancer, researchers at The Johns hopkins university have discovered why elevated levels of the protein NHE9 add to the lethality of the most common and aggressive form of brain cancer, glioblastoma.
Their discovery suggests that drugs designed to target NHE9 could help to successfully fight the deadly disease.
A summary of their work in human tumor cells and mice will be published on Feb 9 in the journal Nature Communications. y laboratory research on cargo transport inside the cells of patients with autism has led to a new strategy
for treating a deadly brain cancer says Rajini Rao, Ph d, . a professor of physiology at the Johns hopkins university School of medicine. his is a great example of the unexpected good that can come from going wherever the science takes us.
All animal and human cells contain many argo packagessurrounded by membranes. These so-called endosomes carry newly minted proteins to specific destinations throughout the cell
and haul away old proteins for destruction. Key to their hipping speedis the level of acidity inside the endosomes.
This is controlled by balancing the activity of protein umpsthat push protons into endosomes to increase their acidity with that of protein eaks
Rao research group previously showed that autism-associated defects in the protein NHE9 are harmful
graduate students and postdoctoral fellows in Rao lab searched through patient databases to see if it had other effects on human health.
Teaming up with Alfredo Quinones-Hinojosa, M d.,a professor of neurosurgery at Johns Hopkins, the researchers examined NHE9 in tumor cells from several patients.
Cells with low levels of NHE9 grew the slowest, the team found, and those with the highest levels grew fastest.
And this was confirmed when the tumor cells, which were manipulated to have high or low NHE9, were transplanted into the brains of mice.
Image credit: Hari Prasad and Rajini Rao. Based on their autism research, the team suspected that the boost NHE9 gave to glioblastomas was explained by abnormal endosome acidity.
Further studies revealed that, in contrast to autism, NHE9 is overactive in brain cancer, causing endosomes to leak too many protons
and become too alkaline. This slows down the hipping rateof cancer-promoting cargo and leaves them on the cell surface for too long.
Research from other laboratories suggested that one such cargo protein is EGFR, which maintains cancer-promoting signals at the cell surface
and helps tumors become more robust so they grow and move faster. It is also found at elevated levels in more than one-half of patients with glioblastomas.
Drugs targeting EGFR in these patients are sometimes effective. As they suspected, the team found that alkaline endosomes slow down the removal of EGFR from cell surfaces.
Lab-grown tumor cells were killed more readily when treated with both a drug countering NHE proteins
and a drug against EGFR than when treated by the EGFR-targeting drug alone. Quinones-Hinojosa says:
so that hopefully we can make this disease less aggressive and less devastating. About this genetics research Other authors of the report include Kalyan Kondapalli, Jose Llongueras, Vivian Capilla-Gonzalez, Hari Prasad, Anniesha Hack, Christopher Smith and Hugo Guerrero
-Cazares of the Johns hopkins university School of medicine. This work was supported by grants from the National Institute of Neurological disorders and Stroke (NS070024), the National Institute of Diabetes and Digestive and Kidney diseases (DK054214
the National Institute of General Medical sciences (GM62142), the American Heart Association (11post7380034), the Johns Hopkins Post-Baccalaureate Research Education Program, the International Fulbright Science and Technology Award,
and the American Physiological Society Porter Physiology Development Fellowship a
#Scientists Find More DNA and Extra Copies of Disease Gene in Alzheimer s Brain cells The surprise discovery offers a new understanding of Alzheimer s disease.
Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer s patients pointing to an unexpected factor that may underpin the most common form of the disease.
A new study published February 4 2015 in the online journal elife shows that Alzheimer s brains commonly have many neurons with significantly more DNA and genomic copies of the Alzheimer s-linked gene APP than normal brains.#
#Our findings open a new window into the normal and diseased brain by providing the first evidence that DNA variation in individual neurons could be related to brain function
and Alzheimer s disease#said Jerold Chun professor at TSRI and its Dorris Neuroscience Center and senior author of the new study.
Alzheimer s disease is an irreversible brain disease that tends to strike older people. It is progressive#impairing memory destroying motor skills and eventually causing death.
The U s. Centers for Disease Control and Prevention estimates 5. 3 million Americans currently have Alzheimer s disease
and that number is expected to double by 2050 as the population ages. Scientists still do not know what triggers the majority of Alzheimer s cases making it difficult to develop a treatment.
Some genes have been identified in families however 95 percent of cases are#sporadic#with no link to a gene or family history of Alzheimer s.
Researchers have known long about disease-related protein accumulations (called amyloid plaques) in the brains of Alzheimer s patients.
They#ve also known that chromosome 21 plays a role in the disease due to Alzheimer s-like symptoms in people with Down syndrome (with three copies of chromosome 21.
This chromosome contains the APP gene which can lead to production of the primary component of the damaging amyloid plaques.
#In 2001 Chun was the first to report that the brain contains many distinct genomes within its cells#much like the colorful tiles in an artist#s mosaic.#
Remarkably the researchers found that more than 90 percent of sporadic Alzheimer s disease brains displayed highly significant DNA increases of hundreds of millions more DNA base-pairs compared with control samples showing that genomic mosaicism was altered in the Alzheimer s brain.
The tests showed that neurons from patients with sporadic Alzheimer s disease were four times as likely to contain more than the normal two copies of APP with some Alzheimer s neurons containing up to 12 copies of APP a phenomenon never seen in the controls.#
so to be able to connect it with a disease is really interesting#said Gwen Kaeser a graduate student studying in Chun#s lab and co-first author of the study with former graduate student Diane Bushman.
because the genomic signatures of sporadic Alzheimer s disease occur within individual brain cells. Indeed a majority of major brain diseases are also sporadic.
For example amyotrophic lateral sclerosis (ALS) can be linked to a gene in one to two percent of cases
Chun believes genomic mosaicism could possibly have a role in other brain diseases. Future studies in the Chun lab will investigate the relationship between mosaicism
and disease the causes of mosaicism and potential new disease drug targets present in the millions of extra base-pairs found in single Alzheimer s disease neurons.
In addition to Chun Kaeser and Bushman other authors of the study#Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer s disease brains#were Jurgen
Stevens K. Rehen of TSRI now at the Federal University of Brazil; and Richard R. Rivera Benjamin Siddoway and Yun C. Yung all of TSRI.
Full open access research for#Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer s disease brains#by Diane M Bushman
In this study we report altered genomic mosaicism in single sporadic Alzheimer s disease (AD) neurons characterized by increases in DNA content and amyloid precursor protein (APP) gene copy number.
These data identify somatic genomic changes in single neurons affecting known and unknown loci which are increased in sporadic AD
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