Aggregates of the Huntington’s disease-associated protein, huntingtin, can spread among neurons, according to a study published last month in Nature Neuroscience, giving credence, experts suggest, to the idea that the propagation of mutant proteins may be a unifying feature of neurodegenerative diseases.
Huntington’s disease, a progressive neurodegenerative disorder that impairs both movement and cognition, is caused by dominant mutations in the huntingtin gene that lead to abnormally long stretches of the amino acid glutamine in the huntingtin protein. These proteins tend to clump in affected neurons, although whether the aggregates are a cause of neurodegeneration or perhaps some kind of cellular response to the mutant protein is still a matter of debate.
The huntingtin gene is expressed throughout the nervous system, so it is hard to tell whether huntingtin aggregates originate within the cells in which they are observed.
To answer this question, researchers from the Novartis Institutes for Biomedical Research in Basel, Switzerland, and their academic colleagues introduced neurons with the wild-type huntingtin gene into mutant brain tissue—both in cell culture and in a mouse model. After several weeks, they observed that aggregates of mutant huntingtin protein had appeared in the wild-type neurons, indicating that the protein from the mutant neurons had spread.
“This paper reports for the first time that mutant huntingtin can spread between neurons,” lead author F. Paolo Di Giorgio, who studies Huntington’s and other neurodegenerative diseases at the Novartis Institutes, told The Scientist.
Neurodegenerative diseases including Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration have been shown to involve the propagation of aggregate pathology from cell to cell. Evidence is mounting that neurodegenerative diseases share mechanisms with prion diseases—exemplified by mad cow disease and its human counterpart, Creutzfeldt-Jakob disease, in which misfolded, deleterious proteins propagate over long distances and cause other molecules to misfold.
“This is the first time that diseases involving what are called polyglutamine-expanded proteins have been found to involve a process of transneuronal propagation,” said Albert La Spada, who studies neurodegenerative disease at the University of California, San Diego, School of Medicine and penned a companion article about the study but was not involved in the work. Polyglutamine expansion is a feature of eight neurodegenerative diseases, including Huntington’s, La Spada said. “That’s significant because it extends the scope of this mechanism more broadly across potentially all neurodegenerative diseases. That’s what makes this study particularly exciting.”
To see if huntingtin aggregates could propagate, the researchers first grew human embryonic stem cells alongside brain slices from either mice with a Huntington’s-like disease or wild-type mice. The stem cells differentiated into neurons and formed connections with the mutant neurons of the brain slices. By six weeks of this co-culture, the introduced wild-type neurons exhibited mutant huntingtin aggregates. They also had shorter and fewer appendages than did neurons co-cultured with wild-type brain slices. Further, introduced neurons that exhibited huntingtin aggregates had significantly narrower cell bodies and fewer projections than those that did not.
“Cells that bear these aggregates show abnormal pathology that is more pronounced [with] respect to cells that don’t bear the aggregates,” said Di Giorgio, “so it seems that when the neurons uptake mutant huntingtin—wild-type neurons that don’t carry any mutation—they will start to show signs of cellular atrophy.”
Huntington’s disease typically begins in the striatum, a brain region involved in movement control, and progresses to the cortex. To examine the way Huntington’s disease might affect this neuronal pathway, the researchers co-cultured striatal and cortical brain slices from wild-type and mutant mice. They found that when mutant cortical neurons and wild-type striatal brain slices were cultured together, functional neuronal connections formed between the brain slices, and mutant huntingtin spread to the wild-type neurons.
When researchers tried the reverse approach—linking mutant striatum and wild-type cortex—the two regions did not form neuronal connections, suggesting that mutant huntingtin within the striatum could disrupt corticostriatal connections.
To explore the corticostriatal pathway in vivo, the researchers used a virus to introduce the polyglutamine-repeat-encoding part of the huntingtin gene into the cortical neurons of wild-type mice. The neurons that were infected with the virus developed aggregates as expected, as did the striatal neurons with which the infected cells made connections.
Finally, in order to probe the mechanism of mutant huntingtin spreading, the researchers returned to their original experimental setup—co-cultures of wild-type human neurons and mutant mouse brain slices—and inhibited the synaptic vesicle pathway using botulinum toxin. Blocking the synaptic transmission reduced the spread of the huntingtin aggregates.
Taken together, these results lend support to the idea that Huntington’s disease shares features with other neurodegenerative diseases, and with prion diseases.
“If neurodegenerative diseases have a unifying feature,” neurobehavioral geneticist X. William Yang from the University of California, Los Angeles, told The Scientist in an e-mail, “then understand[ing] the mechanisms or developing therapies against such common features may have more general implications/utility for all such disorders.”
“If spreading occurs and drives disease progression, then blocking the spreading process could be a viable treatment approach,” added La Spada. “If the spreading process occurs extracellularly … then immunizing patients against a disease protein could be explored as a therapy.”
Doctors in China were surprised to find that a young woman who had lived a normal life for more than two decades was actually missing an important part of her brain, according to a new report of her case. The 24-year-old’s strange condition was discovered when she went to doctors because of a month long bout of nausea and vomiting. The patient told the doctors she had also experienced dizziness her entire life. She didn’t start walking until she was four and had never been able to walk steadily.
When the doctors scanned the woman’s brain, they found she had no cerebellum, a region of the brain thought to be crucial for walking and other movements. Instead, the scans showed a large hole filled with cerebrospinal fluid.
"CT and MRI scans revealed no remnants of any cerebellar tissues, verifying complete absence of the cerebellum," the doctors wrote in the report, published Aug. 22 in the journal Brain.
The cerebellum, which means “little brain” in Latin, is responsible for coordination and fine movements, such as the movements of the mouth and tongue needed for producing speech. People with damage to this brain area typically experience debilitating motor difficulties. Yet contrary to the doctors’ expectations, the Chinese woman’s absence of the cerebellum resulted in only mild to moderate motor problems and slightly slurred pronunciation, according to the researchers. “This surprising phenomenon,” demonstrates the plasticity of the brain early in life, they wrote.
"It shows that the young brain tends to be much more flexible or adaptable to abnormalities," said Dr. Raj Narayan, chair of neurosurgery at North Shore University Hospital and Long Island Jewish Medical Center in New York, who wasn’t involved with the woman’s case. "When a person is either born with an abnormality or at a very young age loses a particular part of the brain, the rest of the brain tries to reconnect and to compensate for that loss or absence," Narayan said.
This remarkable ability of the brain is thought to decline with age. “As we get older, the ability of the brain to tolerate damage is much more limited,” Narayan said. “So, for example, in a 60-year-old person, if I took the cerebellum out, they would be severely impaired.”
This is not the first case of a person found to be missing the cerebellum. In fact, there have been eight other similar cases reported, the researchers said. However, most cases involved infants or children who also showed severe mental impairment, epilepsy and large structural abnormalities in their brains, and most did not survive the condition.
It is possible that more people are affected by this rare condition but they don’t get diagnosed or reported, Narayan said. “In the future, it may become more recognized because of brain imaging,” he added.
Dream On: Why Sleep is So Important
This infographic showcases some studies on just how dangerous—and costly—sacrificing sleep can be, and it concludes with some facts on how you can try and improve your sleep quality if it’s something you struggle with.
Surgical operation, 1910
A sleep-promoting circuit located deep in the primitive brainstem has revealed how we fall into deep sleep. Discovered by researchers at Harvard School of Medicine and the University at Buffalo School of Medicine and Biomedical Sciences, this is only the second “sleep node” identified in the mammalian brain whose activity appears to be both necessary and sufficient to produce deep sleep.
Published online in Nature Neuroscience, the study demonstrates that fully half of all of the brain’s sleep-promoting activity originates from the parafacial zone (PZ) in the brainstem. The brainstem is a primordial part of the brain that regulates basic functions necessary for survival, such as breathing, blood pressure, heart rate and body temperature.
“The close association of a sleep center with other regions that are critical for life highlights the evolutionary importance of sleep in the brain,” says Caroline E. Bass, assistant professor of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences and a co-author on the paper.
The researchers found that a specific type of neuron in the PZ that makes the neurotransmitter gamma-aminobutyric acid (GABA) is responsible for deep sleep. They used a set of innovative tools to precisely control these neurons remotely, in essence giving them the ability to turn the neurons on and off at will.
“These new molecular approaches allow unprecedented control over brain function at the cellular level,” says Christelle Ancelet, postdoctoral fellow at Harvard School of Medicine. “Before these tools were developed, we often used ‘electrical stimulation’ to activate a region, but the problem is that doing so stimulates everything the electrode touches and even surrounding areas it didn’t. It was a sledgehammer approach, when what we needed was a scalpel.”
“To get the precision required for these experiments, we introduced a virus into the PZ that expressed a ‘designer’ receptor on GABA neurons only but didn’t otherwise alter brain function,” explains Patrick Fuller, assistant professor at Harvard and senior author on the paper. “When we turned on the GABA neurons in the PZ, the animals quickly fell into a deep sleep without the use of sedatives or sleep aids.”
How these neurons interact in the brain with other sleep and wake-promoting brain regions still need to be studied, the researchers say, but eventually these findings may translate into new medications for treating sleep disorders, including insomnia, and the development of better and safer anesthetics.
“We are at a truly transformative point in neuroscience,” says Bass, “where the use of designer genes gives us unprecedented ability to control the brain. We can now answer fundamental questions of brain function, which have traditionally been beyond our reach, including the ‘why’ of sleep, one of the more enduring mysteries in the neurosciences.”
More than a century after their discovery, we still don’t know what blood groups like O, A and B are for. Do they really matter? Carl Zimmer investigates.
When my parents informed me that my blood type was A+, I felt a strange sense of pride. If A+ was the top grade in school, then surely A+ was also the most excellent of blood types – a biological mark of distinction.
It didn’t take long for me to recognise just how silly that feeling was and tamp it down. But I didn’t learn much more about what it really meant to have type A+ blood. By the time I was an adult, all I really knew was that if I should end up in a hospital in need of blood, the doctors there would need to make sure they transfused me with a suitable type.
And yet there remained some nagging questions. Why do 40% of Caucasians have type A blood, while only 27% of Asians do? Where do different blood types come from, and what do they do? To get some answers, I went to the experts – to haematologists, geneticists, evolutionary biologists, virologists and nutrition scientists.
In 1900 the Austrian physician Karl Landsteiner first discovered blood types, winning the Nobel Prize in Physiology or Medicine for his research in 1930. Since then scientists have developed ever more powerful tools for probing the biology of blood types. They’ve found some intriguing clues about them – tracing their deep ancestry, for example, and detecting influences of blood types on our health. And yet I found that in many ways blood types remain strangely mysterious. Scientists have yet to come up with a good explanation for their very existence.
My knowledge that I’m type A comes to me thanks to one of the greatest discoveries in the history of medicine. Because doctors are aware of blood types, they can save lives by transfusing blood into patients. But for most of history, the notion of putting blood from one person into another was a feverish dream.
Renaissance doctors mused about what would happen if they put blood into the veins of their patients. Some thought that it could be a treatment for all manner of ailments, even insanity. Finally, in the 1600s, a few doctors tested out the idea, with disastrous results. A French doctor injected calf’s blood into a madman, who promptly started to sweat and vomit and produce urine the colour of chimney soot. After another transfusion the man died.
Such calamities gave transfusions a bad reputation for 150 years. Even in the 19th Century only a few doctors dared try out the procedure. One of them was a British physician named James Blundell. Like other physicians of his day, he watched many of his female patients die from bleeding during childbirth. After the death of one patient in 1817, he found he couldn’t resign himself to the way things were.
“I could not forbear considering, that the patient might very probably have been saved by transfusion” he later wrote.
EXCUSE ME BUT THIS RING. NO ONE NOTICED IT?????
Actually I’ve seen people mention it since the first episode.
It’s Capaldi’s wedding ring. He never takes it off, even when acting.
To add to the story, he refuses to take it off because when his acting career was struggling, his wife never gave up on him. When he landed his first major gig, he decided to not take it off, to represent he was there because of his wife’s support.
This is the sweetest and best thing I’ve eve heard about any behind-the-scenes ever
Remember when he’s told the tradition is to give that chocolate box to someone “you love" and he immediately jumped off the stage and ran to his wife in Seoul without even a second thought?
this is the reason i love and RESPECT him this much… just… *sniffs*
This is a map of Asia. North Americans, you may notice this map is not solely comprised of Japan, Korea, China and Thailand. People in the UK, you may notice India is not a continent. That is, if those of you who generalize entire continents can even pinpoint India on a map.
Indians are Asian, gasp! And not all brown skinned people are Indian, also, gasp! There are an alarming amount of people, of all ages, from all backgrounds, who seem to be unable to process this.
I’m ethnically Asian. Since Asia is an extremely large continent, I could be from any number of countries. I am neither from India, China, Korea, Japan or Pakistan, yet not so surprisingly, I am still Asian.
Yes, there are commonalities across regions, through the conflation of cultures, colonialism, globalization, transnationalism and movement of diasporas. Sometimes these are all the same thing. Rickshaws, rice and curry can be found across the continent.
But let’s not overgeneralize. You can also find Buddhists, Catholics, Muslims and Hindus across Asia. Cantonese Speaking Chinese Muslims! English Speaking Indian Jews!
No, we are not all the same. Orientalism? (Please look up Edward Said for basic concepts) No thank you.
So let’s not use umbrella terms, regarding Asians as a monolith while simultaneously denying the regional identity of millions of people- and how about we also not engage in xenophobia?
Are you someone that thinks this way? Shame on you! You should perhaps invest in buying a map, and take a look at what countries are you know, where.
Geography, people. It’s important.
For anyone out there who might not be able to see this image, it is a coloured map showing Northern Asia, Central Asia, Western Asia, Eastern Asia, Southern Asia, and South-Eastern Asia.
Central Asia consists of Afghanistan (debated), Kazakhstan, Uzbekistan, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan.
Eastern Asia consists of China, Hong Kong, Japan, Macau, Mongolia, North Korea, South Korea, and Taiwan.
Northern Asia consists of Armenia, Azerbaijan, Georgia, and Russia.
South Asia consists of Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka.
South-Eastern Asia consists on Andaman and Nicobar Islands, Brunei, Cambodia, Christmas Island, Cocos Islands, East Timor, Indonesia, Laos, Malaysia, Myanmar (Burma), Philippines, Singapore, Thailand, Vietnam.
Western Asia consists of Armenia, Azerbaijan, Bahrain, Cyprus, Egypt (debated), Georgia, Iran (debated), Iraq, Israel, Joran, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, Turkey, United Arab Emirates, and Yemen.
Fun fact: tennant forgot his line in this scene and said this instead
When was the last time you stood in a grocery store and just listened to everything around you? Depending on where you are, you probably heard all sorts of different things. Especially if you’re in a city, you’ll likely hear all sorts of different accents. You’ll…