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Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Neuroscience, Pediatrics, Research

Stanford team uses brain scans to forecast development of kids’ math skills

Stanford team uses brain scans to forecast development of kids' math skills

multiplication-table-2Back in the third grade, I did not like math. It was boring! It was hard! Why did I have to memorize the times tables, anyway?

Did this mean I would have trouble with math for the rest of my life, or would I get over my eight-year-old’s funk and end up being good at it? At the time, there was no way to know. But now, in a longitudinal study published today in The Journal of Neuroscience, a team of Stanford researchers show that scans of third graders’ brains forecast which children will eventually do well in math and which of them will continue to struggle.

The resting MRI scans collected in the study evaluated the brain’s structure and connectivity between different brain regions in 43 eight-year-olds of normal intelligence. The researchers also gave the children several standardized tests outside the scanner. They then re-tested the kids’ math skills regularly for the next six years.

The brain scans were better than standard IQ, math or other tests at predicting how the children’s math skills would develop. Larger volume and greater connectedness of specific brain regions at age eight was linked to better math skills down the road. From our press release:

“A long-term goal of this research is to identify children who might benefit most from targeted math intervention at an early age,” said senior author Vinod Menon, PhD, professor of psychiatry and behavioral sciences. “Mathematical skills are crucial in our increasingly technological society, and our new data show which brain features forecast future growth in math abilities.”

In addition to identifying at-risk kids, the scans may help scientists design better ways to help them. Because the new work gives a baseline understanding of brain features in children with normal math skills, it may help guide efforts to strengthen the brains of kids with math difficulties. The researchers, who are now exploring how math tutoring changes the brain, encourage parents and teachers not to give up on children who have a hard time with math:

“Just because a child is currently struggling doesn’t necessarily mean he or she will be a poor learner in the future,” said [Tanya] Evans, [PhD, first author of the new study].

As for me, math never became my favorite subject. But I did eventually shake my early aversion to it. Since my job requires me to understand a range of mathematical concepts, I’m grateful — and I hope the new work being done at Stanford will allow today’s struggling third-graders to someday say the same.

Previously: A not so fearful symmetry: Applying neuroscience findings to teaching math, Peering into the brain to predict kids’ responses to math tutoring and New research tracks “math anxiety” in the brain
Photo by jmawork

Neuroscience, Research

Exploring the role of prion-like proteins in memory disorders

Exploring the role of prion-like proteins in memory disorders

Over on the Mind the Brain blog, Stanford psychiatrist Shaili Jain, MD, discusses disorders of memory, including post-traumatic stress disorder and Alzheimer’s, with Nobel Laureate Eric Kandel, MD.

Ongoing research conducted by Kandel has helped scientists better understand the basic molecular mechanisms underlying learning and memory. His latest study showed how prion-like proteins, which are similar to the prions behind bovine spongiform encephalopathy and Creutzfeld-Jakob disease, are key for maintaining long-term memories in mice – and likely other mammals.

In Jain’s conversation with Kandel, she asks him how these new findings may translate clinically and impact patients diagnosed with memory disorders. He responds:

We are already there in some areas. We have far to go in other areas, but I will give you an example. We have a pretty good understanding of Alzheimer’s disease. We know the toxicity of beta amyloid. We do not know why the drugs that are directed against beta amyloid do not work, but one possibility that is being seriously entertained is that by the time the patient comes to see a physician, they have had the disease for ten years. That is a very long time and you lose a lot of nerve cells in ten years, and drugs do not bring nerve cells back once they are dead.

We need to diagnose the disease earlier and a major effort now, in Alzheimer’s research, is early diagnosis. Imaging, cerebral spinal fluid, genetic warning signals etc.

The other thing is it has proven possible to define an independent disorder, age related memory loss. Recent work from our lab, and that of Scott Small, has shown there is a separate entity, independent of AD, called Age Related Memory Loss. We have identified the molecular pathways involved in that disorder. We have treatments that work very effectively in animals. I think the time is going to come soon when these will be tried in people.

All of these came out from a basic science and work with experimental animals. So even though we are in the very early stage of understanding the really complex functions of the brain, we are making progress and all of this will hopefully have some therapeutic impact.

Previously: Memory of everyday events may be compromised by sleep apnea, Malfunctioning glia – brain cells that aren’t nerve cells – may contribute big time to ALS and other neurological disorders and The state of Alzheimer’s research: A conversation with Stanford neurologist Michael Greicius

Behavioral Science, Genetics, Neuroscience

Wishing for a genetic zodiac sign: How much can genes really tell us about personality?

Wishing for a genetic zodiac sign: How much can genes really tell us about personality?

Brain MRIGiven all the recent news on how gene expression influences our brain, from Alzheimer’s to addiction and even our personalities, readers might come away thinking that we’re close to breaking the code and using genetics to understand why we behave the way we do. But, things aren’t that simple.

In a post on the science blog Last Word on Nothing, Eric Vance explores what getting your personal genetic sequence means for your personality – something he calls, tongue-in-cheek, “a genetic tarot card.”

Vance delves into an explanation of one specific mutation in the COMT gene. The gene creates an enzyme that neutralizes dopamine, a neurotransmitter. The gene comes in two forms, and the difference in these two forms is just one base-pair, the individual links in our DNA code. One version of the resulting enzyme is efficient at clearing away extra dopamine. But if the gene codes for the other version, “then the enzyme becomes a wastrel… Work piles up and the brain accumulates a bunch of extra dopamine.”

Because dopamine is such a powerful regulator of mood, and by extension personality, Vance then describes, in surprising detail, personality types he expects people with either version of the gene to have. But genetic information like this is meant to be used at the population, not personal, level. In fact, none of the people in his circle of friends who have had their genome sequenced turns out to be who he expects them to be (which begs the question, how many people does he know who’ve had their DNA sequenced?). Disappointed, he laments:

But that’s not how I want it work. While I don’t like the idea of boiling human emotions down to a couple squishy turning gears, I do like how tidy it is. I want to be able to look up my genome and make broad generalizations about myself. I want to have a genetic tarot card that I can inspect and say “ohhh, that’s why I always forget people’s names” or “that’s why I got in that fight in the third grade.”

Vance concludes, “But that’s not what nature gave us. Nature has given us messy, confusing and vastly complicated brains.” We are more, it turns out, than the sum of our base pairs.

Previously: New research sheds light on connection between dopamine and depression symptoms

Photo by deradrian

Aging, Ask Stanford Med, Chronic Disease, Neuroscience, Women's Health

Exploring Alzheimer’s toll on women

Exploring Alzheimer’s toll on women

Julianne Moore AlzheimersIn last year’s “Still Alice,” Julianne Moore’s portrays a woman beset by early-onset Alzheimer’s Disease. It’s fitting that the academy-award winning film (Moore garnered a Best Actress award for her role) about Alzheimer’s features a woman as the central character because the illness disproportionately affects women.

The BeWell@Stanford blog recently featured a Q&A with Stanford neurologist and Alzheimer’s researcher Michael Greicius, MD, MPH about Alzheimer’s and women. The piece covers the effects of the disease, but I was intrigued to read about the challenges for caregivers of people with the disease (who are also disproportionately women):

Most of the caregivers of people with Alzheimer’s Disease are women. Do you have any advice for them in terms of how they can take care of themselves while taking care of a loved one with the disease?

This gets to the damned-if-you-do, damned-if-you-don’t aspect of AD and women. On the one hand, women are more likely to develop AD; on the other hand, they are also more likely to find themselves as the primary caregiver for someone with AD. It is now well known that caring for someone with AD has a powerful, negative impact on physical and emotional well-being. Particularly as the disease progresses and patients require more care, there is a large physical toll taken when, for example, having to lift patients out of a chair or off the toilet or out of bed. Sleep becomes fractured for the patient. which means it becomes fractured for the caregiver.

Some of the questions also dealt with the fact that despite the recent advances in Alzheimer’s research, we still don’t completely understand how the disease works or how it can be prevented:

What can we do to reduce our risk for developing the disease?

We do not know of anything that definitely reduces a person’s risk of developing Alzheimer’s, although there is strong data to suggest that regular aerobic exercise and a heart-smart diet will reduce risk. Head trauma is an important risk factor for AD and another type of dementia, so minimizing exposure to head trauma can also reduce risk of AD. Numerous companies make explicit or implicit claims about their “nutraceutical” or vitamin or “brain-training” software being able to stave off AD. None of these claims are true and most, if not all, of these purveyors are modern-day snake-oil salesmen and saleswomen.

But Greicius is optimistic and pointed out that Stanford recently became an NIH-sponsored Alzheimer’s Disease Research Center, which means we can build upon Stanford’s past “ground-breaking Alzheimer’s research.”

Previously: Are iron, and the scavenger cells that eat it, critical links to Alzheimer’s?Alzheimer’s forum with Rep. Jackie Speier spurs conversation, activismScience Friday explores women’s heightened risk for Alzheimer’s and The toll of Alzheimer’s on caretakers
Photo by Maria Morri

Humor, Media, Medicine and Society, Neuroscience, Research, Stanford News

Did extraterrestrials chew up my news release, or does artificial intelligence still have a ways to go?

Did extraterrestrials chew up my news release, or does artificial intelligence still have a ways to go?

UFO

Almost two years ago, in a Scope blog entry titled “Can Joe Six-Pack compete with Sid Cyborg?” I posed the question: “Just how long will it be before we can no longer tell our computers from ourselves?”

I think it’s safe to say we’re not there yet. Either that, or extraterrestrials have been reading my news releases and finding them puzzling.

Last week we put out a news release I’d written about a dramatic discovery by Stanford radiologists Mike Zeineh, MD, PhD, Brian Rutt, PhD, and their colleagues. In brief, they’d analyzed postmortem slabs of brain tissue from people diagnosed with Alzheimer’s, compared them with equivalent brain-tissue slabs taken from people who’d died without any Alzheimer’s-like symptoms, and noticed some striking and intriguing differences. In a key brain region essential to memory formation, Zeineh and Rutt had spotted – only in Alzheimer’s brains, not normal ones – iron deposits engulfed by mobile inflammatory cells. This observation’s potentially big implications were plenty newsworthy.

It so happened that, on the day we issued the release, a high-powered five-day-long meeting on Alzheimer’s sponsored by the eponymous Alzheimer’s Association was in session in Washington, D.C. As a result, many of the brain-oriented science writers to whom my news release was targeted were preoccupied.

I was a little anxious about that. So, the other day, I turned to my favorite search engine to see if the release had managed to get some traction in the popular press. As I’d feared, the Washington conference had sucked up a lot of the oxygen in the earthly neuroscience arena.

But apparently, the release had done better in Outer Space. I saw that it had been picked up by, for example, Red Orbit (a website that I’ve always assumed, based on its name, emanates from Mars).

My eyes were next drawn to a link to an unfamiliar outfit called AZ News, which bills itself in a tagline as an “International Online News Site.” I clicked on the link, and saw a news report with the same title as my release. I started reading the text below.

The first words were: “In autopsy mind hankie from people not diagnosed with Alzheimer’s…” I don’t know what an “autopsy mind hankie” is, but I suspect it’s a mind-blower.

I checked our release. That’s not what I’d written at all. What I’d said was, “In postmortem brain tissue from people not diagnosed with Alzheimer’s…”

It seemed pretty clear that the release had been translated into some language – I had no idea which – and then, for some reason, reverse-translated back into English. I read on.

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Autism, Behavioral Science, Neuroscience, Pediatrics, Research, Stanford News

A new insight into the brain chemistry of autism

A new insight into the brain chemistry of autism

TrueHugFor several years now, scientists have been testing the hypothesis that one particular hormone, oxytocin, plays a role in autism. It seems logical: After all, this molecule nicknamed the “love hormone” promotes bonding between romantic partners and is one of the main signals involved in childbirth, breastfeeding and helping new mothers form strong bonds with their babies. And social-interaction difficulties are a known characteristic of autism, a developmental disorder that affects one in every 68 kids.

But in the flurry of interest around oxytocin, a related signaling molecule has been largely overlooked. Called vasopressin, it’s structurally very similar to oxytocin. Both are small proteins made of nine amino acids each, and the amino-acid sequence is identical at seven of the nine spots in the two hormones. Vasopressin is best known for its role in regulating blood pressure, but it also has social roles, which have mostly been studied in rodents.

Noting the dearth of autism-vasopressin research, a Stanford team decided to study vasopressin levels and social behavior in children diagnosed with autism and controls who had not been diagnosed with autism. Our press release about their study, which was published today in PLOS ONE, explains:

The research team found a correlation between low levels of vasopressin, a hormone involved in social behavior, and the inability of autistic children to understand that other people’s thoughts and motivations can differ from their own. …

“Autistic children who had the lowest vasopressin levels in their blood also had the greatest social impairment,” said the study’s senior author, Karen Parker, PhD, associate professor of psychiatry and behavioral sciences.

Parker and her colleagues examined “theory of mind,” the ability to deduce that others have a mind of their own – and that they may perceive the world differently than you do. It’s an important underpinning to forming empathetic relationships with other people. In kids with autism, the lower their vasopressin levels, the worse their scores on a test of theory of mind, the study found. Children without autism did not show this link; they all had pretty good theory of mind scores, whether their vasopressin levels were low or high.

It’s worth adding that low vasopressin level did not diagnose whether a child had autism; the hormone’s levels ranged from low to high in both groups of children. So autism is not simply a state of vasopressin deficiency. However, the researchers are interested in whether giving vasopressin might help relieve autism symptoms and are now carrying out a clinical trial to test its effects.

The work also provides an interesting complement to oxytocin findings published by the same team last year. In the oxytocin study, the scientists found that children with autism could have low, medium or high oxytocin levels, just like other children. However, oxytocin levels were linked to social ability in all children, not just those with autism.

Based on the new findings, it’s possible, Parker told me, that vasopressin is uniquely important for children with autism. She’s eager to expand her work in this overlooked corner of brain-chemistry research.

Previously: Stanford research clarifies biology of oxytocin in autism, “Love hormone” may mediate wider range of relationships than previously thought and Volunteers sought for autism drug study
Artwork by Dimka

Imaging, Immunology, Mental Health, Neuroscience, Research, Stanford News

Are iron, and the scavenger cells that eat it, critical links to Alzheimer’s?

Are iron, and the scavenger cells that eat it, critical links to Alzheimer's?

iron linkIf you’ve been riding the Alzheimer’s-research roller-coaster, brace yourself for a new twist on that wrenching disease of old age.

In a study published in Neurobiology of Aging, Stanford radiologists Mike Zeineh, MD, PhD,  and Brian Rutt, PhD, and their colleagues used a ultra-powerful magnetic-resonance-imaging (MRI) system to closely scrutinize postmortem tissue from the brains of people with and without Alzheimer’s disease. In four out of five of the Alzheimer’s brains they looked at, but in none of the five non-Alzheimer’s brains, they found what appear to be iron-containing microglia – specialized scavenger cells in the brain that can sometimes become inflammatory – in a particular part of the hippocampus, a key brain structure that’s absolutely crucial to memory formation as well as spatial orientation and navigation.

Zeineh and Rutt told me they don’t know how the iron gets into brain tissue, or why it accumulates where it does. But iron, which in certain chemical forms can be highly reactive and inflammation-inducing, is ubiquitous throughout the body. Every red blood cell that courses through our microvasculature is filled with it. So one possibility – not yet demonstrated – is that iron deposits in the hippocampus could result from micro-injury to small cerebral blood vessels there.

As surprising as the iron-laden, inflamed microglia Zeineh, Rutt and their associates saw in Alzheimer’s but not normal brains was what they didn’t see. Surprisingly, in the brain region of interest there was no consistent overlap of either iron or microglia with the notorious amyloid plaques that have been long held by many neuroscientists and pharmaceutical companies to be the main cause of the disorder. These plaques are extracellular aggregations of a small protein called beta-amyloid that are prominent in Alheimer’s patients’ brains, as well as in mouse models of the disease.

Because they weren’t able to visualize small, soluble beta-amyloid clusters (now believed to to be the truly toxic form of the protein), Rutt and Zeineh don’t rule out a major role for beta-amyloid in the early developmental stages of pathology in Alzheimer’s.

Continue Reading »

Neuroscience, Research, Science, Stanford News

Nobelist neuroscientist Tom Südhof still spiraling in on the secrets of the synapse

Nobelist neuroscientist Tom Südhof still spiraling in on the secrets of the synapse

spiral staircase“History,” said Winston Churchill (or was it Arnold Toynbee or Edna St. Vincent Millay?), “is just one damn thing after another.” In many respects, so is good science.

And that’s just how it should be, Stanford neuroscientist and molecular physiologist Tom Südhof, MD, told me a few years ago when I interviewed him for a story I wrote in connection with the Lasker Award, a prestigious prize he’d won shortly before receiving the 2013 Nobel Prize in physiology or medicine:

Asked to recall any defining “eureka!” moments that had catapulted his hunches forward to the status of certainty, Südhof noted that in his experience, science advances step by step, not in jumps. “I believe strongly that most work is incremental,” he said. The systematic solution of highly complex problems requires a long view and plenty of patience.

Climbing a long ladder to the Nobel one small step at a time, Südhof continually raised the power of his conceptual microscope over the decades as he probed the intricate workings of synapses: the all-important junctions in the nervous system where information, in the form of chemical messengers called neurotransmitters, gets passed from one nerve cell to another.

From an explanation of Südhof’s synaptic studies:

The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of taking a step forward, experiencing a fleeting twinge of regret, recalling an incident from the morning commute or tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and peripheral nervous system.

A philosopher might say that synapses collectively constitute the physiological substrate for the soul. A futurist might write (as I once did):

With nanobots monitoring every critical neural connection’s involvement in a thought or emotion or experience, you’ll be able to back up your brain – or even try on someone else’s – by plugging into a virtual-reality jack. The brain bots feed your synapses the appropriate electrical signals and you’re off and running, without necessarily moving.

Continue Reading »

Neuroscience, Stanford News, Videos

Are decisions driven by subconscious desires or shaped by conscious goals?

Are decisions driven by subconscious desires or shaped by conscious goals?

Throughout our lives, we often encounter perplexing situations involving other individuals or read in the news about someone’s seemingly irrational decision and say to ourselves: What were they thinking? In this Stanford+Connects video, Bill Newsome, PhD, director of the Stanford Neurosciences Institute, and his wife Brie Linkenhoker, PhD, a neuroscientists-turned-strategist who directs Worldview Stanford, examine the process of decision making and the role of impulses and self-control. Watch the full talk to learn more about the mechanisms driving us to make decisions.

Previously: Exploring the science of decision making and Exploring the intelligence-gathering and decision-making processes of infants

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