Scientists Keep a Molecule from Moving Inside Nerve Cells to Prevent Cell Death

Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is a progressive disorder that devastates motor nerve cells. People diagnosed with ALS slowly lose the ability to control muscle movement, and are ultimately unable to speak, eat, move, or breathe. The cellular mechanisms behind ALS are also found in certain types of dementia.

A groundbreaking scientific study published in Nature Medicine has found one way an RNA binding protein may contribute to ALS disease progression. Cells make RNA to carry instructions for making proteins from DNA to protein-constructing machinery.

The culprit protein, TDP-43, normally binds to small pieces of newly read RNA and helps shuttle the fragments around inside nerve cell nuclei. The study describes for the first time the molecular consequences of misplaced TDP-43 inside nerve cells, and demonstrates that correcting its location can restore nerve cell function. Misplacement of TDP-43 in nerve cells is a hallmark of ALS and other neurological disorders including frontotemporal dementia (FTD), Alzheimer’s, Parkinson’s, and Huntington’s diseases. Studies that characterize common mechanisms behind these diseases could have widespread implications and may also accelerate development of broad-based therapies.

To find the misplaced TDP-43, the researchers viewed nerve cells donated by people who died from ALS or FTD under high powered microscopes. They discovered TDP-43 accumulates in nerve cell mitochondria, critical structures responsible for generating the enormous amount of energy nerve cells require. By physically isolating the affected mitochondria the researchers were able to pinpoint TDP-43’s exact location inside the subcellular structures. They were also able to characterize variations of the protein most likely to get misplaced.

This important work was led by Xinglong Wang, PhD, from the department of pathology at Case Western Reserve University School of Medicine and a team of scientists from his laboratory.

“By multiple approaches, we have identified the mitochondrial inner membrane facing matrix as the major site for mitochondrial TDP-43,” explained Wang. “Mitochondria might be major accumulation sites of TDP-43 in dying neurons in various major neurodegenerative diseases.”

The researchers discovered that once inside the mitochondria, TDP-43 resumes its RNA binding role and attaches itself to mitochondrial genetic material. This disrupts the mitochondria’s ability to generate energy for the cell. Wang’s team was able to precisely identify the RNA in mitochondria that was bound by TDP-43 and observe the resultant disassembly of mitochondrial protein complexes. This finding provides much needed clarity on the consequences of TDP-43 misplacement inside nerve cells and opens the door for deeper studies involving a range of neurological disorders. Although the study focused on ALS and FTD, according to Wang “mislocalization of TDP-43 represents a key pathological feature correlating strongly with symptoms in more than half of Alzheimer’s disease patients.”

Mutations in the gene encoding TDP-43 have long been linked to neurodegenerative diseases like ALS and FTD. Wang’s team found that disease-associated mutations in TDP-43 enhance its misplacement inside nerve cells. The researchers also identified sections of TDP-43 that are recognized by mitochondria and serve as signals to let it inside. These sections could serve as therapeutic targets, as the study found blocking them prevents TDP-43 from localizing inside mitochondria. Importantly, Wang’s team was able to keep TDP-43 out of nerve cell mitochondria in mice using small proteins which “almost completely” prevented nerve cell toxicity and disease progression.

“We, for the first time, provide the novel concept that the inhibition of TDP-43 mitochondrial localization is sufficient to prevent TDP-43-linked neurodegeneration,” said Wang. “Targeting mitochondrial TDP-43 could be a novel therapeutic approach for ALS, FTD and other TDP-43-linked neurodegenerative diseases.”

Wang has begun to develop small proteins that prevent TDP-43 from reaching mitochondria in human nerve cells, and has a patent pending for the therapeutic molecule used in the study.

There is no treatment currently available for ALS or FTD. The average life expectancy for people newly diagnosed with ALS is just three years, according to The ALS Association.

repeat after me:

it’s okay to be human!!!! uwu

bigots are the problem, homo sapiens are not.

it’s not okay to hate people for not being mutants.

it’s not okay to kill all of the humans.

hating or killing an innocent person solely because of their lack of a mutated x-gene makes you an asshole, erik.

reblog if you’re for mutant equality, NOT mutant supremacy!!!!!!!! uwu uwu uwu

False-colored scanning electron micrograph of human embryonic stem cell (gold) growing within a cradling cluster of supporting fibroblasts. Image courtesy of Annie Cavanaugh, Wellcome Images

The trouble within stem cells

Inducing human pluripotent stem cells to become any kind of desired cell has the potential to transform medicine: Doctors could, for example, repair, rebuild – maybe even build anew – damaged or diseased organs.

Of course, nature has had millions of years to master the process – and it doesn’t often even attempt things like regeneration. Humans are strictly rank beginners, still struggling to fully understand the countless complexities of biological construction and overcome the myriad obstacles to success.

Chief among them is the concern that induced stem cells might carry or create mutations that, in the process of differentiation and growth, would introduce or exacerbate disease, rather than cure it. A 2011 paper published in Nature by Kun Zhang, PhD, at UC San Diego, for example, found that genetic material of reprogrammed cells may in fact be compromised.

Nowhere is this more worrisome than in efforts to find stem cell-based therapies to treat cancer, which is essentially a disease of gene mutations. The greater the “mutational load,” the greater the chance of cancer.

In a new paper, published in the journal Cell Reports, Louise Laurant, MD, PhD, adjunct assistant professor in the Department of Reproductive Medicine at UC San Diego School of Medicine, and colleagues describe analyses of two sets of human embryonic stem cell (hESC) lines.

They showed for the first time that different genetic aberrations tend to occur at different stages of development in hESCs. During preimplantation embryo development and early derivation, mutations are mainly deletions or “loss of heterozygosity,” which occurs when some copies of primary nucleobases (cytosine, guanine, adenine, thymine and uracil) are missing.

Conversely, long-term culturing of hESCs aberrations are more frequently duplications of genetic information.

The findings reinforce the importance and need to measure and monitor the genetic integrity of hESCs, and specifically point to areas of concern.

Serious efforts are being made in this regard. For example, Steven Dowdy, PhD, professor in the UC San Diego Department of Cellular & Molecular Medicine, recently published a paper describing a simple, easy RNA-based method of generating human induced pluripotent stem cells. You can read the news release here.


[Gabriel remembered the day he realized Adrien would be different. He was doing fine for the first six months, growing and hitting each of his milestones. But after he learned to crawl, he never reached another one.
And he never would. Adrien was born with a neurological disorder caused by a rare gene mutation. He would never learn to walk or properly speak or read. He acted like a feral child and by law he was treated like one. And now that Gabriel’s wife was gone, Gabriel had to care for his ill son on his own]


Two blue chicks

The image above shows the skeleton of a normal chick (top left) and a chicken with a severe mutation (top right). 

The mutation is in a gene called TALPID3 which is important for development. Chickens which have lost the function of TALPID3 have brain deformities, small lungs, liver fibrosis and extra fingers.

Scientists at the Roslin Institute have now found that humans with a rare genetic disorder that affects brain development, called Joubert syndrome, also have mutations in TALPID3. 

By investigating the impact of the gene at the cellular level in chickens, the researchers have provided further insight into the specifics of Joubert syndrome in people.

Read more 

Interested in the Human Genome?

A few years ago, the US Department of Energy’s Genomic Science Program produced a poster highlighting the loci (gene location) of hundreds of genetic conditions.

Unfortunately they had a very small supply, and this was quite a few years ago, so it has long since been out of stock. However, their website for the poster is still up, and they offer a high quality PDF file of the poster for download. I highly recommend checking it out.

They also have individual image files of each chromosome for easier legibility, which look something like this:

I only remembered this porter tonight when replying to a post about another science poster, but it occurred to me that the science side of tumblr might find it as neat as I do.

Source/credit: U.S. Department of Energy Genomic Science program’s  Biological and Environmental Research Information System (BERIS). Their website states that permission to use these images is not needed however credit is requested.  Website:

The scary reason many people get cancer: bad luck

Despite the proven risks associated with fast food, sunburns, cigarettes and lack of physical activity, it turns out that most cancer diagnoses are actually a matter of chance. A study published in 2015 found that most cancer is caused by random gene mutations, which is terrifying. But the researchers behind the study were anxious to clarify that this doesn’t mean there’s no rhyme or reason to why people get cancer.

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The 3230 genes you can’t do without

Fiddle just a little bit with any one of about 3200 genes in the human body and you could be toast. That’s the conclusion of a new study, which finds that about 15% of our 20,000 genes are so critical to our livelihood that even minor mutations can kill us before we’re born. The findings should help researchers better track down the genes that cause human disease.

By comparing sets of genes from tens of thousands of people, researchers have found some that the body can’t seem to live without. Jane Ades/NHGRI

X-Linked Recessive Inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed (1) in males (who are necessarily homozygous for the gene mutation because they have only one X chromosome) and (2) in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes).

X-linked inheritance means that the gene causing the trait or the disorder is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. Carrier females who have only one copy of the mutation do not usually express the phenotype, although differences in X chromosome inactivation can lead to varying degrees of clinical expression in carrier females since some cells will express one X allele and some will express the other. The current estimate of sequenced X-linked genes is 499 and the total including vaguely defined traits is 983.

The most common X-linked recessive disorders are:

  • Red-green color blindness, a very common trait in humans and frequently used to explain X-linked disorders. Between seven and ten percent of men and 0.49% to 1% of women are affected. Its commonness may be explained by its relatively benign nature. It is also known as daltonism.
  • Hemophilia A, a blood clotting disorder caused by a mutation of the Factor VIII gene and leading to a deficiency of Factor VIII. It was once thought to be the “royal disease” found in the descendants of Queen Victoria. This is now known to have been Hemophilia B (see below).
  • Hemophilia B, also known as Christmas Disease, a blood clotting disorder caused by a mutation of the Factor IX gene and leading to a deficiency of Factor IX. It is rarer than hemophilia A. As noted above, it was common among the descendants of Queen Victoria.
  • Duchenne muscular dystrophy, which is associated with mutations in the dystrophin gene. It is characterized by rapid progression of muscle degeneration, eventually leading to loss of skeletal muscle control, respiratory failure, and death.
  • Becker’s muscular dystrophy, a milder form of Duchenne, which causes slowly progressive muscle weakness of the legs and pelvis.
  • X-linked ichthyosis, a form of ichthyosis caused by a hereditary deficiency of the steroid sulfatase (STS) enzyme. It is fairly rare, affecting one in 2,000 to one in 6,000 males.
  • X-linked agammaglobulinemia (XLA), which affects the body’s ability to fight infection. XLA patients do not generate mature B cells. B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins) which defends the body from infections (the humoral response). Patients with untreated XLA are prone to develop serious and even fatal infections.
  • Glucose-6-phosphate dehydrogenase deficiency, which causes non-immune hemolytic anemia in response to a number of causes, most commonly infection or exposure to certain medications, chemicals, or foods. Commonly known as “favism”, as it can be triggered by chemicals existing naturally in broad (or fava) beans.

Some scholars have suggested discontinuing the terms dominant and recessive when referring to X-linked inheritance due to the multiple mechanisms that can result in the expression of X-linked traits in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism.


Link seen between seizures and migraines in the brain

Seizures and migraines have always been considered separate physiological events in the brain, but now a team of engineers and neuroscientists looking at the brain from a physics viewpoint discovered a link between these and related phenomena.

Scientists believed these two brain events were separate phenomena because they outwardly affect people very differently. Seizures are marked by electrical hyperactivity, but migraine auras – based on an underlying process called spreading depression – are marked by a silencing of electrical activity in part of the brain. Also, seizures spread rapidly, while migraines propagate slowly.

“We wanted to make a more realistic model of what underlies migraines, which we were working on controlling,” said Steven J. Schiff, Brush Chair Professor of Engineering and director of the Penn State Center for Neural Engineering. “We realized that no one had ever kept proper track of the neuronal energy being used and all of the ions, the charged atoms, going into and out of brain cells.”

Potassium and sodium contribute the ions that control electricity in the brain. The Penn State researchers added fundamental physics principles of conservation of energy, charge and mass to an older theory of this electricity. They kept track of the energy required to run a nerve cell, and kept count of the ions passing into and out of the cells.

The brain needs a constant supply of oxygen to keep everything running because it has to keep pumping the ions back across cell membranes after each electrical spike. The energy supply is directly linked to oxygen concentrations around the cell and the energy required to restore the ions to their proper places is much greater after seizures or migraines.

“We know that some people get both seizures and migraines,” said Schiff. “Certainly, the same brain cells produce these different events and we now have increasing numbers of examples of where single gene mutations can produce the presence of both seizure and migraines in the same patients and families. So, in retrospect, the link was obvious – but we did not understand it.”

The researchers, who also included Yina Wei, recent Penn State Ph.D. in engineering science and mechanics, currently a postdoctoral fellow at University of California-Riverside, and Ghanim Ullah, former Penn State postdoctoral fellow, now a professor of physics at University of South Florida, explored extending older models of brain cell activity with basic conservation principles. They were motivated by previous Penn State experiments that showed the very sensitive link between oxygen concentration with reliable and rapid changes in nerve cell behavior.

What they found was completely unexpected. Adding basic conservation principles to the older models immediately demonstrated that spikes, seizures and spreading depression were all part of a spectrum of nerve cell behavior. It appeared that decades of observations of different phenomena in the brain could share a common underlying link.

“We have found within a single model of the biophysics of neuronal membranes that we can account for a broad range of experimental observations, from spikes to seizures and spreading depression,” the researchers report in a recent issue of the Journal of Neuroscience. “We are particularly struck by the apparent unification possible between the dynamics of seizures and spreading depression.”

While the initial intent was to better model the biophysics of the brain, the connection and unification of seizures and spreading depression was an emergent property of that model, according to Schiff.

“No one, neither us nor our colleagues anticipated such a finding or we would have done this years ago,” said Schiff. “But we immediately recognized what the results were showing and we worked intensively to test the integrity of this result in many ways and we found out how robust it was. Although the mathematics are complex, the linking of these phenomena seems rock solid.”

The ability to better understand the difference between normal and pathological activity within the brain may lead to the ability to predict when a seizure might occur.

“We are not only interested in controlling seizures or migraines after they begin, but we are keen to seek ways to stabilize the brain in normal operating regimes and prevent such phenomena from occurring in the first place,” said Schiff. “This type of unification framework demonstrates that we can now begin to have a much more fundamental understanding of how normal and pathological brain activities relate to each other. We and our colleagues have a lot on our plate to start exploring over the coming years as we build on this finding.”

Gene therapy could be used to treat ADHD

A new study in the journal Nature may hold the key to combating attention deficit hyperactivity disorder: modifying your genes.

Researchers from the Massachusetts Institute of Technology and New York University’s Langone Medical Center found that ADHD is connected to the thalamic reticular nucleus, where your brain blocks out things that are distracting you. Working with mice, the team discovered that a gene mutation in some of the rodents meant the TRN wasn’t working properly — and that’s where things get interesting.

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The Continuing Evolution of Genes

Each of us carries just over 20,000 genes that encode everything from the keratin in our hair down to the muscle fibers in our toes. It’s no great mystery where our own genes came from: our parents bequeathed them to us. And our parents, in turn, got their genes from their parents.

But where along that genealogical line did each of those 20,000 protein-coding genes get its start?

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(Image caption: Alterations of the human 16p11.2 chromosomal region lead to a variety of cognitive disorders, including autism. Credit: Pasieka/Science Source)

New findings reveal genetic brain disorders converge at the synapse

Several genetic disorders cause intellectual disability and autism. Historically, these genetic brain diseases were viewed as untreatable. However, in recent years neuroscientists have shown in animal models that it is possible to reverse the debilitating effects of these gene mutations. But the question remained whether different gene mutations disrupt common physiological processes. If this were the case, a treatment developed for one genetic cause of autism and intellectual disability might be useful for many others.

In a paper published today in the online edition of Nature Neuroscience, a research team led by Mark Bear, the Picower Professor of Neuroscience in MIT’s Picower Institute for Learning and Memory, showed that two very different genetic causes of autism and intellectual disability disrupt protein synthesis at synapses, and that a treatment developed for one disease produced a cognitive benefit in the other. The research was performed by postdoc and lead author Di Tian, graduate student Laura Stoppel, and research scientist Arnold Heynen, in collaboration with scientists at Cold Spring Harbor Laboratory and Roche Pharmaceuticals.

Researching the role of fragile X syndrome

One heritable cause of intellectual disability and autism is fragile X syndrome, which arises when a single gene on the X chromosome, called FMR1, is turned off during brain development. Fragile X is rare, affecting one in about 4,000 individuals. In previous studies using mouse models of fragile X, Bear and others discovered that the loss of this gene results in exaggerated protein synthesis at synapses, the specialized sites of communication between neurons.

Of particular interest, they found that this protein synthesis was stimulated by the neurotransmitter glutamate, downstream of a glutamate receptor called mGluR5. This insight led to the idea, called the mGluR theory, that too much protein synthesis downstream of mGluR5 activation gives rise to many of the psychiatric and neurological symptoms of fragile X. Bear’s lab tested this idea in mice, and found that inhibiting mGluR5 restored balanced protein synthesis and reversed many defects in the animal models.

Different genes, same consequences

Another cause of autism and intellectual disability is the loss of a series of genes on human chromosome 16, called a 16p11.2 microdeletion. Some of the 27 affected genes play a role in protein synthesis regulation, leading Bear and colleagues to wonder if 16p11.2 microdeletion syndrome and fragile X syndrome affect synapses in the same way. To address this question, the researchers used a mouse model of 16p11.2 microdeletion, created by Alea Mills at Cold Spring Harbor Laboratory. 

Using electrophysiological, biochemical, and behavioral analyses, the MIT team compared this 16p11.2 mouse with what they already had established in the fragile X mouse. Synaptic protein synthesis was indeed disrupted in the hippocampus, a part of the brain important for memory formation. Moreover, when they tested memory in these mice, they discovered a severe deficit, similar to fragile X.

Restoring brain function after disease onset

These findings encouraged the MIT researchers to attempt to improve memory function in the 16p11.2 mice with the same approach that has worked in fragile X mice. Treatment with an mGluR5 inhibitor, provided by a team of scientists at Roche led by Lothar Lindemann, substantially improved cognition in these mice. Of particular importance, this benefit was achieved with one month of treatment that began well after birth. The implication, according to Bear, is that “some cognitive aspects of this disease, previously believed to be an intractable consequence of altered early brain development, might instead arise from ongoing alterations in synaptic signaling that can be corrected by drugs.”

Current research indicates that well over 100 distinct gene mutations can manifest as intellectual disability and autism. The current findings are heartening, as they indicate not only that drug therapies might be effective to improve cognition and behavior in affected individuals, but also that a treatment developed for one genetic cause might apply more broadly to many others.

Antibiotic-Resistant Genes Found in Mummy

Genes associated with antibiotic resistance have been found in an 11th-century mummy’s colon and feces, long before antibiotics were introduced.

The find suggests that gene mutations responsible for antibiotic resistance occurred naturally in 1000-year-old bacteria and are not necessarily linked to the overuse of antibiotics.

The research, published in the online issue of PlosOne, began as an international team of scientists analyzed the microbiome of the remains that were mummified naturally in the cold climate of the Andes Mountains. 

Found in Cuzco, the ancient capital of the Inca empire, the mummy was brought to Italy in the second half of the 19th century by professor Ernesto Mazzei. It was then donated to the Museum of Anthropology and Ethnology of the University of Florence, Italy, where it is currently stored with 11 other mummies. Read more.