Posts tagged neurodegeneration

A research team led by Jackson Laboratory Professor and Howard Hughes Investigator Susan Ackerman, Ph.D., has pinpointed a surprising mechanism behind neurodegeneration in mice, one that involves a defect in a key component of the cellular machinery that makes proteins, known as transfer RNA or tRNA.

The researchers report in the journal Science that a mutation in a gene that produces tRNAs operating only in the central nervous system results in a “stalling” or pausing of the protein production process in the neuronal ribosomes. When another protein the researchers identified, GTPBP2, is also missing, neurodegeneration results.

“Our study demonstrates that individual tRNA genes can be tissue-specifically expressed in vertebrates,” Ackerman says, “and mutations in such genes may cause disease or modify other phenotypes. This is a new area to look for disease mechanisms.”

Neurodegeneration—the process through which mature neurons decay and ultimately die—is poorly understood, yet it underlies major human diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).

While the causes of neurodegeneration are still coming to light, there is mounting evidence that neurons are exquisitely sensitive—much more so than other types of cells—to disruptions in how proteins are made and how they fold.

tRNAs are critical in translating the genetic code into proteins, the workhorses of the cell. tRNAs possess a characteristic cloverleaf shape with two distinct “business” ends—one that reads out the genetic code in three-letter increments (or triplets), and another that transports the protein building block specified by each triplet (known as an amino acid).

In higher organisms, tRNAs are strikingly diverse. For example, while there are 61 distinct triplets that are recognized by tRNAs in humans, the human genome contains roughly 500 tRNA genes. To date little is known about why they are so numerous, whether they carry out overlapping or redundant functions, or whether they possibly have roles beyond the making of proteins.

“Multiple genes encode almost all tRNA types,” Ackerman says. “In fact, AGA codons are decoded by five tRNAs in mice. Until now, this apparent redundancy has caused us to completely overlook the disease-causing potential of mutations in tRNAs, as well as other repetitive genes.”

Ackerman and her colleagues at The Jackson Laboratory in Bar Harbor, Maine, and Farmington, Conn., The Scripps Research Institute in LaJolla, Calif., and Kumamoto University in Japan pinpointed a mutation in the tRNA gene n-Tr20 as a genetic culprit behind the neurodegeneration observed in mice lacking GTPBP2.

Remarkably, the tRNA’s activity is confined to the brain and other parts of the central nervous system, in both mice and humans. The tRNA encoded by n-Tr20 recognizes the triplet code, AGA (which specifies the amino acid arginine).

The n-Tr20 defect disrupts how proteins are made. Specifically, it causes the “factories” responsible for synthesizing proteins, called ribosomes, to stall when they encounter an AGA triplet.

Such stalling can be largely overcome, thanks to the work of a partner protein called GTPBP2. But when this partner is missing—as it is in the mutant mice that Ackerman and her colleagues studied—the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.

(Source: jax.org)

Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.

That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.

The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new research from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.

In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also detail new discoveries about the basic biology of dystonia, made from studying the mice.

They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.

The U-M team’s success in creating a mouse model for the disease came only after 17 years of stubborn, persistent effort – often in the face of setbacks and failure.

Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.

The gene defect responsible, called DYT1, causes brain cells to make a less-active form of a protein called torsinA. But despite more than a decade of effort by Dauer’s team and many others around the world, no one has been able to translate this information into an animal model with dystonia’s characteristic movements.

Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to severely impair torsinA function during early brain development. This novel twist caused the new mice to closely mimic the human disease: they don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.

With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.

In an unexpected development, they found that the lack of torsinA in the brains of dystonic mice led to the death of neurons – a process called neurodegeneration – in just a few highly localized parts of the brain that control movement. Like the dystonic movements, this neurodegeneration began in young mice, progressed for a time, and then became fixed. 

“We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult,” says Dauer, an associate professor in the U-M departments of Neurology and Cell & Developmental Biology.

“In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology — one just has to listen carefully.”

(Image caption: The brains of the mice with dystonia (shown in the right column) had much higher levels of neuron death than those without the condition (left column) — and this neurodegeneration was limited to certain areas involved in controlling muscle movements.)

More discoveries to come

Dauer and his team don’t yet know why only one-third of human DYT1 gene mutation carriers develop primary dystonia during their school years, and why those who don’t develop the disease before their early 20s will never go on to develop it.

They believe some critical events during the brain’s development in infancy and childhood may have to do with it - and they’re already working to explore that question in mice.

They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.

In all these cases, as in people with DYT1 mutations, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.

In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.

The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.

(Source: uofmhealth.org)

A team of UCLA researchers has identified a new gene involved in Parkinson’s disease, a finding that may one day provide a target for a new drug to prevent and potentially even cure the debilitating neurological disorder.

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease, and there is no cure for the progressive and devastating illness. About 60,000 Americans are diagnosed with Parkinson’s disease each year. It is estimated that as many as 1 million Americans live with Parkinson’s disease, which is more than the number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

In Parkinson’s disease, multiple neurons in the brain gradually break down or die. This leads to the movement impairments, such as tremor, rigidity, slowness in movement and difficulty walking, as well as depression, anxiety, sleeping difficulties and dementia, said Dr. Ming Guo, the study team leader, associate professor of neurology and pharmacology and a practicing neurologist at UCLA.

A handful of genes have been identified in inherited cases of Parkinson’s disease. Guo’s team was one of two groups worldwide that first reported in 2006 in the journal Nature that two of these genes, PTEN-induced putative kinase 1 (PINK1) and PARKIN, act together to maintain the health of mitochondria – the power house of the cell that is important in maintaining brain health. Mutations in these genes lead to early-onset Parkinson’s disease.

Guo’s team has further shown that when PINK1 and PARKIN are operating correctly, they help maintain the regular shape of healthy mitochondria and promote elimination of damaged mitochondria. Accumulation of unhealthy or damaged mitochondria in neurons and muscles ultimately results in Parkinson’s disease.

In this study, the team found that the new gene, called MUL1 (also known as MULAN and MAPL), plays an important role in mediating the pathology of the PINK1 and PARKIN. The study, performed in fruit flies and mice, showed that providing an extra amount of MUL1 ameliorates the mitochondrial damage due to mutated PINK/PARKIN, while inhibiting MUL1 in mutant PINK1/PARKIN exacerbates the damage to the mitochondria. In addition, Guo and her collaborators found that removing MUL1 from mouse neurons of the PARKIN disease model results in unhealthy mitochondria and degeneration of the neurons.

The five-year study appears June 4, 2014, in eLife, a new, open access scientific journal for groundbreaking biomedical and life research sponsored by the Howard Hughes Medical Institute (United States), the Wellcome Trust (United Kingdom) and Max Plank Institutes (Germany).

"We are very excited about this finding," Guo said. "There are several implications to this work, including that MUL1 appears to be a very promising drug target and that it may constitute a new pathway regulating the quality of mitochondria."

Guo characterized the work as “a major advancement in Parkinson’s disease research.”

"We show that MUL1 dosage is key and optimizing its function is crucial for brain health and to ward off Parkinson’s disease," she said. "Our work proves that mitochondrial health is of central importance to keep us from suffering from neurodegeneration. Further, finding a drug that can enhance MUL1 function would be of great benefit to patients with Parkinson’s disease."

Going forward, Guo and her team will test these results in more complex organisms, hoping to uncover additional functions and mechanisms of MUL1. Additionally, the team will perform small molecule screens to help identify potential compounds that specifically target MUL1. Further, they will examine if mutations in MUL1 exist in some patients with inherited forms of Parkinson’s.

(Source: eurekalert.org)

Researchers at King’s College London have discovered how a molecular ‘scaffold’ which allows key parts of cells to interact, comes apart in dementia and motor neuron disease, revealing a potential new target for drug discovery.

The study, published today in Nature Communications, was funded by the UK Medical Research Council, Wellcome Trust, Alzheimer’s Research UK and the Motor Neurone Disease Association.

Researchers looked at two components of cells: mitochondria, the cell ‘power houses’ which produce energy for the cell;and the endoplasmic reticulum (ER) which makes proteins and stores calcium for signalling processes in the cell. ER and mitochondria form close associations and these interactions enable a number of important cell functions. However the mechanism by which ER and mitochondria become linked has not, until now, been fully understood.

Professor Chris Miller, from the Department of Neuroscience at the Institute of Psychiatry at King’s and lead author of the paper, says: “At the molecular level, many processes go wrong in dementia and motor neuron disease,and one of the puzzles we’re faced with is whether there is a common pathway connecting these different processes. Our study suggests that the loosening of this ‘scaffold’ between the mitochondria and ER in the cell may be a key process in neurodegenerative diseases such as dementia or motor neuron disease.”

By studying cells in a dish, the researchers discovered that an ER protein called VAPB binds to a mitochondrial protein called PTPIP51, to form a ‘scaffold’ enabling ER and mitochondria to form close associations. In fact, by increasing the levels of VAPB and PTPIP51, mitochondria and ER re-organised themselves to form tighter bonds.

Many of the cell’s functions that are controlled by ER-mitochondria associations are disrupted in neurodegenerative diseases, so the researchers studied how the strength of this ‘scaffold’ was affected in these diseases. TDP-43 is a protein which is strongly linked to Amyotrophic Lateral Sclerosis (ALS, a form of motor neuron disease) and Fronto-Temporal Dementia (FTD, the second most common form of dementia), but exactly how the protein causes neurodegeneration is not properly understood.

The researchers studied how TDP-43 affected mouse cells in a dish. They found that higher levels of TDP-43 resulted in a loosening of the scaffold which reduced ER-mitochondria bonds,affecting some important cellular functions that are linked to ALS and FTD.

Professor Miller concludes: “Our findings are important in terms of advancing our understanding of basic biology, but may also provide a potential new target for developing new treatments for these devastating disorders.”

(Source: kcl.ac.uk)

Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer’s disease without ever showing clinical symptoms in their lifetime.

Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer’s.

“Most Alzheimer’s research is searching for genes that predict the disease, but we’re taking a different approach. We’re looking for genes that predict who among those with Alzheimer’s pathology will actually show clinical symptoms of the disease,” said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer’s Center.

The article, “Genetic modification of the relationship between phosphorylated tau and neurodegeneration,” was published online recently in the journal Alzheimer’s and Dementia.

The researchers used a marker of Alzheimer’s disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer’s disease tau forms “tangles” that disrupt cellular messages.

Analyzing a sample of 700 subjects from the Alzheimer’s Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation — a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.

“This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau,” Hohman said.

“It appears that certain individuals with a genetic predisposition toward a ‘bad’ neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration.”

Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer’s disease.

“The work highlights the possible mechanism behind asymptomatic Alzheimer’s disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer’s symptoms,” Hohman said.

(Source: news.vanderbilt.edu)

An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the height of the Ottoman Empire in Turkey about 16 generations ago.

(Image caption: An fMRI scan of the brain of a patient with CLP1 mutation reveals severe atrophy of the brainstem (red line) and cerebellum (blue) as well as lack of formation of the corpus callosum (green), which connects both sides of the cerebrum (yellow), which is also atrophied. The lines outline approximately the expected sizes of the brain areas. A study traced the mutation to a single individual born in Turkey during the Ottoman Empire, some 16 generations ago.)

The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.

“The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer’s or Lou Gehrig’s Disease,” said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.

Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson’s group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells’ protein-making machinery.

The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.

Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.

The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.

Gunel said that the high prevalence of consanguineous marriages [between closely related people] in Turkey and the Middle East leads to these rare recessive genetic neurodegenerative disorders. Affected children inherit mutations in the same gene from both of their parents, who are closely related to each other, such as first cousins. Without consanguinity between parents, children are very unlikely to inherit two mutations in the same gene.

“By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function” Gunel said. “We learn a lot about normal biology by studying what happens when things go wrong.”

(Source: news.yale.edu)

A study of older adults at increased risk for Alzheimer’s disease shows that moderate physical activity may protect brain health and stave off shrinkage of the hippocampus – the brain region responsible for memory and spatial orientation that is attacked first in Alzheimer’s disease. Dr. J. Carson Smith, a kinesiology researcher in the University of Maryland School of Public Health who conducted the study, says that while all of us will lose some brain volume as we age, those with an increased genetic risk for Alzheimer’s disease typically show greater hippocampal atrophy over time. The findings are published in the open-access journal Frontiers in Aging Neuroscience.

"The good news is that being physically active may offer protection from the neurodegeneration associated with genetic risk for Alzheimer’s disease," Dr. Smith suggests. "We found that physical activity has the potential to preserve the volume of the hippocampus in those with increased risk for Alzheimer’s disease, which means we can possibly delay cognitive decline and the onset of dementia symptoms in these individuals. Physical activity interventions may be especially potent and important for this group."

Dr. Smith and colleagues, including Dr. Stephen Rao from the Cleveland Clinic, tracked four groups of healthy older adults ages 65-89, who had normal cognitive abilities, over an 18-month period and measured the volume of their hippocampus (using structural magnetic resonance imaging, or MRI) at the beginning and end of that time period. The groups were classified both for low or high Alzheimer’s risk (based on the absence or presence of the apolipoprotein E epsilon 4 allele) and for low or high physical activity levels.

Of all four groups studied, only those at high genetic risk for Alzheimer’s who did not exercise experienced a decrease in hippocampal volume (3 percent) over the 18-month period. All other groups, including those at high risk for Alzheimer’s but who were physically active, maintained the volume of their hippocampus.

"This is the first study to look at how physical activity may impact the loss of hippocampal volume in people at genetic risk for Alzheimer’s disease," says Dr. Kirk Erickson, an associate professor of psychology at the University of Pittsburgh. "There are no other treatments shown to preserve hippocampal volume in those that may develop Alzheimer’s disease. This study has tremendous implications for how we may intervene, prior to the development of any dementia symptoms, in older adults who are at increased genetic risk for Alzheimer’s disease."

Individuals were classified as high risk for Alzheimer’s if a DNA test identified the presence of a genetic marker – having one or both of the apolipoprotein E-epsilon 4 allele (APOE-e4 allele) on chromosome 19 – which increases the risk of developing the disease. Physical activity levels were measured using a standardized survey, with low activity being two or fewer days/week of low intensity activity, and high activity being three or more days/week of moderate to vigorous activity.

"We know that the majority of people who carry the E4 allele will show substantial cognitive decline with age and may develop Alzheimer’s disease, but many will not. So, there is reason to believe that there are other genetic and lifestyle factors at work," Dr. Smith says. "Our study provides additional evidence that exercise plays a protective role against cognitive decline and suggests the need for future research to investigate how physical activity may interact with genetics and decrease Alzheimer’s risk."

Dr. Smith has previously shown that a walking exercise intervention for patients with mild cognitive decline improved cognitive function by improving the efficiency of brain activity associated with memory. He is planning to conduct a prescribed exercise intervention in a population of healthy older adults with genetic and other risk factors for Alzheimer’s disease and to measure the impact on hippocampal volume and brain function.

(Source: umdrightnow.umd.edu)