Could Trashing Junk Proteins Quash Alzheimer’s, Parkinson’s, ALS and Huntington’s?

JULY 26, 2016

Scientists search for the Marie Kondo of the brain—a drug to clear cellular debris

Although clutter can be a nuisance, it does not typically pose a health threat—unless you’re an aging neuron. As brain cells get older, some proteins within and around the cell misfold. They twist into the wrong shape, unable to do their routine job. Then they glom together to form menacing clumps. If left to accumulate, this “junk” can overwhelm nerve cells’ quality control systems, triggering incurable brain disorders such as Alzheimer’s, Parkinson’s and Huntington’s.

So whereas these diseases produce distinct symptoms and billions of dollars have been spent researching potential drugs that target their unique molecular culprits, some scientists are placing their bets on cross-cutting approaches that might work across multiple disorders. Rather than going after proteins such as amyloid beta for Alzheimer’s or alpha-synuclein for Parkinson’s, one researcher has set on a different approach: “I settled on the idea that perhaps we should just get rid of as many abnormally folded, nasty-looking proteins as possible,” says Karen Duff, a neuroscientist at Columbia University. Strategies that boost the cell’s quality control programs, rather than disarm specific pathologic proteins, have looked promising in lab animals that serve as models for human neurodegenerative disorders including Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Several molecules have entered human testing. It is still a long road to approved therapies but a growing body of basic research is fueling a search for drugs that interact with cellular cleanup processes to provide one-size-fits-all approaches for treating a megaclass of brain disorders.

Cells have two main systems for clearing excess or damaged proteins. Most of the quick cleanup occurs in cylindrical waste-disposal units called proteasomes, which chop unneeded material into smaller bits that can be recycled into new proteins. Proteasomes also keep cellular trash under control by breaking up misfolded proteins. When these scoundrels band together and the gang gets too large, the cell calls on a second degradation process—autophagy. Derived from Greek terms meaning “self-eating,” the autophagy system sends protein aggregates and malfunctioning cellular components into acidic compartments called lysosomes, where enzymes chew them up.

In the early stages of Alzheimer’s and other so-called proteinopathies—disorders caused by a malformed protein particular proteins adopt the wrong shape and join with similar misfits to form conglomerates that pile up in the brain. For awhile the cell’s cleanup crews keep the junk at bay, sending protein aggregates for degradation as soon as they start to pile up. Rates of autophagy, however, slow with age. Over time, growing heaps of rogue proteins overwhelm the system and the cell gets sick and dies—or, at least, that has been the conventional thinking.

But the problem goes much deeper; it is not simply that freak proteins aggregate and clog the brain. Scientists are discovering that many of the proteins that twist out of shape normally carry out important jobs in the very disposal systems that are supposed to help cells get rid of them, says neurobiologist Ralph Nixon of New York University. The problem has been traced down to the level of specific genes. Some disease mutations turn regular proteins awry by making them fold into the wrong shape. Misfolded proteins often misbehave, which can muck up the cell’s cleaning system and make the organism more susceptible to any number of proteinopathies.

One famous misfit is presenilin-1. This protein is part of the enzymatic engine that churns out amyloid beta—a key molecular culprit in Alzheimer’s disease—by snipping it out of a larger precursor protein called APP. Glitches in the presenilin-1 gene can cause the rare inherited form of Alzheimer’s that strikes at a younger age. Apart from amyloid, though, presenilin-1 has a critical, beneficial function. Working with Ana Maria Cuervo, a professor at Albert Einstein College of Medicine, Nixon and co-workers found that presenilin-1 helps control the acidity of lysosomes. Neurons with abnormal presenilin-1 clear waste poorly and accumulate harmful protein aggregates. More recently Nixon’s team discovered that APP hampers waste disposal systems in nerve clusters that falter and trigger memory decline in the early stages of Alzheimer’s. Along with the earlier study on presenilin-1, these findings highlight the potential for therapies that target protein degradation pathways to help cells deal with buildup of harmful pathologic molecules.

The need for new approaches comes into stark relief as the Alzheimer's Association begins its annual conference this week in Toronto. Alzheimer's is a disease for which there are still no treatments that fundamentally alter the course of the disease, as trial after trial of drug candidates have ended in failure.

Research in Parkinson’s and Huntington’s has uncovered additional examples of disease proteins that, when mutated, stymie protein clearance pathways in neurons. Cuervo’s group found that a mutant protein associated with a heritable version of Parkinson’s gums up lysosomal channels. That leads the protein alpha-synuclein to build up and form toxic clumps in brain areas that control motor function. Last year Cuervo collaborated with Sheng Zhang, a professor at The University of Texas Health Science Center at Houston on experiments showing that huntingtin—the Huntington’s disease protein—helps the cell’s autophagy system identify what it should eliminate. Researchers had focused so much on huntingtin’s toxicity that it was surprising to discover this molecule has a regular day job, Cuervo notes. Rather than being the bad guy that ties up the cleaning system, huntingtin “also happens to be part of the cleaning crew,” she says. “That changes the way we have to approach the problem.”

In recent years Cuervo and co-workers have discovered that giving the cleaning crew a little boost can go a long way. The tough part is figuring out which parts to tweak. “There are many ways to clean the house—a vacuum, a broom,” Cuervo says. Similarly, in cells “there are many ways to bring proteins to the lysosome.” Lysosomes are the final destination for misshapen proteins that get degraded in the autophagy system. One type of autophagy traps chunks of cellular material into “bags” that fuse with lysosomes. A different branch of autophagy—a specialty of Cuervo’s lab—involves molecular chaperones that escort misbehaving proteins through special tunnels into the lysosome.

Several years ago her team designed a chemical that helps cells produce more tunnel components. When tested in cultured cells, the compound specifically activated chaperone-mediated autophagy without touching other pathways. More importantly, in recent studies yet to be published the chemical appears to improve anxiety, depression and memory in mice that mimic some features of Alzheimer’s. The researchers also plan to test the compound in mice modeling Parkinson’s disease.

Tampering with chaperones can be tricky, though. Sometimes chaperones hang onto a bad protein for too long. The major chaperones are not very discriminating. They recognize all unfolded proteins—“anything that’s disordered or stretched out”—and cover those exposed, sticky regions to prevent clumping, says neuroscientist Chad Dickey of the University of South Florida. So it is easy for chaperones to get confused with tau, a protein that accumulates in the brains of people with Alzheimer’s. Normally tau binds to microtubules—molecular conveyor belts that move chromosomes and vesicles within cells. In the early stages of the disease, however, tau proteins undergo changes that nudge them off microtubules. Because tau has a loose molecular structure, chaperones treat free-floating tau as a misfolded protein. They hold onto it, trying to put it back onto microtubules, rather than sending it for degradation. As a result, tau accumulates inside cells to form the infamous clumps that are considered hallmark pathology in neurodegenerative disorders such as Alzheimer’s and progressive supranuclear palsy.

Once a protein lands with a chaperone, any of a number of molecular co-factors swoop in to decide the protein’s fate. In separate studies published in June research teams identified two chaperone complexes that appear to work by ushering disease-linked proteins out of cells. The Florida group identified a co-factor that hooks up with tau, alpha-synuclein and other disease-associated molecules to evict them. “We think it’s a last-ditch effort by neurons to get rid of bad proteins,” Dickey says. Meanwhile a team led by Yihong Ye, a cell biologist at the National Institutes of Health, discovered another pathway that uses different protein workhorses to accomplish a similar off-load. The latter mechanism seems to only dispatch alpha-synuclein whereas the other system can dump several neurodegenerative disease–associated proteins.

The scientists are not sure if the newly discovered pathways are connected or if they relate to a previously identified system that helps clear amyloid beta and other toxins out of the brain. Still, researchers are intrigued by the possibility that cells may use these clearance mechanisms to propagate misfolded proteins throughout the brain—in which case targeting the mechanisms could conceivably slow disease progression.

Compounds that target autophagy or inhibit chaperones have been tested in many clinical trials, mostly in cancer patients. Cancer was the first disease researchers connected with autophagy. Generally scientists have thought autophagy protects against cancer, although some evidence suggests it can help tumor cells cope with nutrient scarcity and other stresses. Because the impact of autophagy on cancer seems to go both ways, cancer trials have tested therapies that enhance autophagy as well as drugs that block it. For neurodegenerative diseases, such research is still in its early phase. One problem is that many of the experimental molecules are too big to enter the brain, Dickey says. Another challenge: the drugs are not very selective. They may influence other processes within the cell.

Nevertheless several autophagy-enhancing compounds have entered human testing for treatment of brain disorders. One, rilmenidine, is a prescription medicine for treating high blood pressure. Recently scientists completed a safety trial of rilmenidine in 16 U.K. adults with early Huntington’s disease. Data analyses are ongoing, says University of Cambridge molecular geneticist David Rubinsztein, one of the trial investigators. Bioblast Pharma—an Israel-based biotech company focused on rare diseases—is launching a phase I trial of trehalose, a sugar found in plants, fungi and invertebrates. The study will enroll healthy volunteers to receive the autophagy-inducing compound intravenously. Last month researchers led by Thomas Kukar, a professor at Emory University, published a paper showing that trehalose can reverse lysosomal deficiencies in mouse models of frontotemporal dementia. And Duff’s lab has unpublished data suggesting that trehalose lessens tau pathology and improves behavior in mouse models of neurodegeneration.

“It seems you just want to clear out all the garbage in the brain,” Duff says.

http://www.scientificamerican.com/article/could-trashing-junk-proteins-quash-alzheimer-s-parkinson-s-als-and-huntington-s/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciam%2Fmind-and-brain+%28Topic%3A+Mind+%26+Brain%29

SaveSave

Watch Out for Brain Game Claims

JULY 26, 2016

 ~~~I USE THE FREE SITE - IT IS YOUR DECISION WHETHER TO SUBSCRIBE OR NOT. APPARENTLY THE CLAIM IS QUESTIONABLE.  By Margaret

Study wasn't powered to detect dementia outcomes

TORONTO -- It's time to hit the reset button on recent headlines about 'brain games' potentially reducing dementia risk.

Many media reports missed the mark on a study presented here at the Alzheimer's Association International Conference that suggested a computer game focused on brain processing speed may be able to diminish dementia risk 10 years down the road.

The New Yorker wrote that "no brain game ... had ever been shown in a large, randomized trial to prevent dementia. That was the case until today."

TIME says the study provides "the strongest evidence yet for the power of brain training to reduce the risk of dementia."

Surely the 'brain games' industry is hopeful for some positive news after recent negative press. In 2014, about 70 researchers from Stanford and the Max Planck Institute signed on to a letter saying there wasn't enough evidence that any of these games worked. A year later, Lumosity paid a federal fine of $2 million to settle false marketing claims.

Those companies will get no redemption from these latest findings.

The data presented here come from a secondary analysis of a trial that wasn't powered to look at dementia outcomes. And results presented at the meeting haven't been through a rigorous peer review process.

The ACTIVE study, which was supported by the National Institute on Aging and the National Institute on Nursing Research, reported its 10-year outcomes in 2014.

ACTIVE was indeed a huge trial, randomizing 2,785 healthy adults ages 65 to 70 who didn't have cognitive impairment to one of three cognitive training interventions or to an inactive control.

Training programs targeted either memory, reasoning, or processing speed, and participants attended 10 sessions once a week for 5 weeks; though some could do more than that.

The study showed that early improvements in memory wore off after 10 years – but effects on reasoning and processing speed remained, with the latter being "remarkably strong," Jonathan King, PhD, of the National Institute on Aging who was an author of that study, told MedPage Today.

Speed of processing training involves strengthening the "unified field of vision," or being able to process at least two objects in one image, one of which is focal and the other in the periphery. The goal is to be able to divide your attention between the two.

It's like the world's most boring video game," King said. "It can be difficult, and if you're the kind of person who wants to get faster and better you'll pay attention, but it's not enticing. There are no Pokemon running around."

The 10-year study didn't report dementia outcomes, because, again, it wasn't powered to detect them.

But King and colleagues retroactively developed a methodology to look at dementia risk over 5 years. In 2012, they reported in a secondary analysis that cognitive training didn't affect rates of incident dementia.

King also noted that 5 years may not have been long enough to capture conversion to dementia. So Jerri Edwards, PhD, of the University of Southern Florida, who had been involved in previous work on the ACTIVE study, applied a similar methodology to assess 10-year outcomes. (King did not participate in this study.)

Edwards found that processing speed was associated with a 33% reduced risk of developing dementia or cognitive impairment over 10 years (HR 0.67, 95% CI 0.49 to 0.91, P=0.012).

She said during a press briefing here that the findings for memory training and reasoning training were not significant, but she did not provide these data.

Dorene Rentz, PsyD, of Harvard, who moderated the oral session where the findings were presented, said Edwards didn't provide hazard ratios at all. King said this information came out during the press briefing.

"She just made very broad claims that I didn't think she backed up," Rentz told MedPage Today. "The whole presentation was like that. You were left walking away with your hands in the air not knowing what to make of it."

Edwards did not return calls for comment.

King said it's difficult to dismiss the data completely out of hand. Speed of processing training "was the largest training effect, and it did last 10 years," he told MedPage Today.Although this latest analysis compared 700 controls and 700 in the processing speed group, it was not designed to be a dementia prevention trial in the first place.

"If it were, it would have to have had many more people," King said.

Announcing these data could have a big impact on uptake of speed processing training, which is currently available online to subscribers. Now known as Brain HQ Double Decision from Posit Sciences, it was originally developed by Edwards' mentor Karlene Ball, PhD, of the University of Alabama.

Ball sold certain rights to the program to Posit, which developed it commercially.

On its website, Posit puts an emphasis on the science behind its software – yet the program used in the ACTIVE study is different from the current version. The original technology was developed 14 years ago and the training was completed on a PC in a research center. The commercially available version looks different and can be done on any consumer device.

King said the technology should translate well, but technically the evidence doesn't pertain to this exact product.

Edwards was a consultant to Posit in 2008 and worked for another company that owned the intellectual property surrounding speed-of-processing training software. She also serves on the data safety and monitoring board of NIH grants awarded to employees of Posit.

Co-author Frederick Unverzagt, PhD, received a site license for cognitive training programs from Posit for investigator-initiated research projects.

King said peer review will have the final say on this secondary analysis of the ACTIVE study.

Slicing the data different ways could make the effect shrink, or disappear completely – but King said being left with even a 10% reduction in dementia would be something other researchers would want to follow up on.

Those follow-up trials should include a larger numbers of patients, as well as an official diagnosis of dementia (this was not recorded in ACTIVE; it was determined later).

"This was a very creative secondary use of the data using techniques that most would accept under the conditions," King said. "But in these intervention trials, the devil is in the details, and we have to make sure there's no hidden confounding influence that would be a threat to the validity of the findings."

PRIMARY SOURCE:

Alzheimer's Association International Conference
Source Reference: Edwards JD "The ACTIVE Study: What we have learned and what is next? Cognitive training reduces incident dementia across 10 years" AAIC 2016; Abstract S2-01-02.

http://www.medpagetoday.com/MeetingCoverage/AAIC/59316?xid=NL_breakingnews_2016-07-26&eun=g972365d0r

How This INCREDIBLE Man Spends His Last Days Before Parkinson's Sets In Is Life

 July 26 ,2016

What do you do when you're told you only have five years of normal life left to live? What this man does next is INCREDIBLE!

When Rafi Elder was diagnosed with Parkinson's Disease a degenerative neurological condition that affects the way people move) eight years ago, he felt like his world had come crashing down. 

Rafi was an accomplished Professor of Economics with an incredible list of achievements including a PhD and the news was so devastating to him that he didn't even tell his family. 

Doctor's regrettably told him he only had a few years left to enjoy his time before the affects of the disease would transform his life irreversibly.

However, this courageous man didn't take the heartbreaking news lying down.

Despite that fact that he had absolutely no experience or background in dancing whatsoever, the 62-year-old decided to take up the skill.

Dancing helps improve all abilities in the body and especially the motor skills that deteriorate due to Parkinson's disease.

Rafi's journey into dance has not only has transformed his whole life and he's won endless competitions, but crucially has delayed the onset of his disease. 

He's tried everything from Ballroom dancing to Cha-Cha.

"When I'm dancing I feel like a a winner" the patient explains. "Dancing saved my life, it feels like a miracle."

As well as cracking out his new moves in various dance competitions, Elder has set up over 20 support groups around Israel to help other sufferer's of the degenerative disease.

Elder is changing the world of treatment through the power of dance and movement.

He literally said "NO" to Parkinson's

 

His dancing partner calls him an inspiration and it's clear from the 2.4 million views video views that he's racked up, that the whole world agrees! 

 Video Link:

https://video-mia1-1.xx.fbcdn.net/v/t43.1792-2/13712952_1031957256872483_546983413_n.mp4?efg=eyJybHIiOjE1MDAsInJsYSI6MzI3MywidmVuY29kZV90YWciOiJzdmVfaGQifQ%3D%3D&rl=1500&vabr=831&oh=61ad26ab90c57f3da54c03f4a4780e01&oe=5797BF2D

http://www.heart.co.uk/style/lifestyle/quirky/inspirational-man-dances-cure-parkinsons-disease/#igbPIslAgeuuqF7i.97

This is what 'free will' looks like in your brain

July 21, 2016

An illustration of the human brain indicates where researchers found activity relating to free-will decisions.: Johns Hopkins University

Scientists have for the first time watched the human brain making a purely voluntary decision to act.

Unlike in brain imaging studies where researchers watch as people respond to cues or commands, Johns Hopkins researchers found a way to observe people’s brain activity as they made choices entirely on their own.

“We now have the ability to learn more about how we make decisions in the real world.”

The findings, which pinpoint parts of the brain involved in decision-making and action, were recently published in the journal Attention, Perception, and Psychophysics.

“How do we peek into people’s brains and find out how we make choices entirely on our own?” asks Susan Courtney, a professor of psychological and brain sciences and senior author of the study. “What parts of the brain are involved in free choice?”

The team devised a novel experiment tracking a person’s focus of attention without using intrusive cues or commands. Participants, positioned in MRI scanners, were left alone to watch a split screen as rapid streams of colorful numbers and letters scrolled past on each side.

They were asked simply to pay attention to one side for a while, then to the other side; when to switch sides was entirely up to them. Over an hour, the participants switched their attention from one side to the other dozens of times.

‘A kind of high-tech mind-reading’

Researchers monitored the participants’ brains as they watched the media stream, both before and after they switched their focus.

For the first time, researchers were able to see both what happens in a human brain the moment a free choice is made, and what happens during the lead-up to that decision—how the brain behaves during the deliberation over whether to act.

“We uncovered important information about what may be the neural underpinnings of volition, or free will.”

The actual switching of attention from one side to the other was closely linked to activity in the parietal lobe, near the back of the brain. The activity leading up to the choice—that is, the period of deliberation—occurred in the frontal cortex, in areas involved in reasoning and movement, and in the basal ganglia, regions deep within the brain that are responsible for a variety of motor control functions including the ability to start an action.

The frontal-lobe activity began earlier than it would have if participants had been told to shift attention, clearly demonstrating that the brain was preparing a purely voluntary action rather than merely following an order.

Together, the two brain regions make up the core components underlying the will to act, the authors conclude.

“What’s truly remarkable about this project,” says Leon Gmeindl, a research scientist at Johns Hopkins and lead author of the study, “is that by devising a way to detect brain events that are otherwise invisible—that is, a kind of high-tech ‘mind reading’—we uncovered important information about what may be the neural underpinnings of volition, or free will.”

Now that scientists have a way to track choices made from free will, they can use the technique to determine what’s happening in the brain as people wrestle with other, more complex decisions.

For instance, researchers could observe the brain as someone tried to decide between snacking on a doughnut or on an apple—watching as someone weighed a short-term desire for sweets against long-term health rewards, and perhaps being able to pinpoint the tipping point between the two.

“We now have the ability to learn more about how we make decisions in the real world,” Courtney says.

The National Institutes of Health provided funding.

https://www.weforum.org/agenda/2016/07/this-is-what-free-will-looks-like-in-your-brain

An estimated 350m people suffer from depression. Could this help reverse it?

July 25, 2016

Researchers have investigated a new direct intervention technique involving manipulating various circuits of the brain.

Manipulating the brain has been a tool used in the treatment of mental illness for centuries, and treatments have often been controversial. From psychosurgery, including lobotomy and leucotomy, to electro-convulsive therapy, which is still used to treat depression and psychotic illness today, more modern methods include deep brain stimulation and transcranial magnetic stimulation.

These direct interventions to the brain aim to relieve the symptoms of severe mental disorders, but are generally a last resort for sufferers or used in the context of specialist clinical centres and research trials.

We know that the brain undergoes changes when a person is depressed or has a similar mood disorder. But part of the problem with neuroscientific research is that it is unclear whether these structural changes cause, or are caused by, the illness.

In an intriguing new study of depression published in the journal Neuron, researchers have investigated a new direct intervention technique to combat the symptoms and effects of depression. The team induced abnormal brain activity similar to depression in mice, and then manipulated various circuits of the brain to successfully control and reverse the effects. This suggests that brain changes could indeed be responsible for, and predate, the development of mental disorders. The implication is that with the right techniques, these changes could be reversed and so improve the patient’s mental disorder.

The new technique works by implanting electrodes in four key areas in the mouse’s brain – the prefrontal cortex, and three sub-areas of the limbic system: the nucleus accumbens, the ventral tegmental area and the amygdala. By measuring electrical signals between these areas, neuroscientists were able to determine the functional connections between them and understand how these parts of the brain communicate with each other during normal brain activity.

The mice were then repeatedly exposed to chronic stress in the form of “social defeat”, which refers to losing a confrontation in a social setting, and is known to cause behaviours in animals similar to human depression. Previously observed connections between areas of the brain were actually altered by this stress, creating a “neural signature” of depression in the brain as the researchers recorded how the neural signalling changed.

Amazingly, the team were able to reverse this abnormality in the stressed mice’s brain activity. By stimulating a key area of brain tissue which interfaces with other nodes to form a network between the prefrontal cortex and the amygdala, normal communication between the areas of the brain was restored, returning the mice’s brain activity to their pre-stressed state. Their behaviour returned to normal and their stress disappeared.

This marks the first time a clear parallel has been demonstrated between a model of depression and a functional neural network.

What’s more, these findings are well backed-up. The prefrontal cortex and limbic areas are already known to be connected to depression in humans. The amygdala is thought to have a key role in processing how important emotional material is to an individual, and how they respond to it – as the mice respond to their stressful situations. The wider limbic system and prefrontal cortex are important in regulating the impact that our emotions have on our cognitive abilities, such as memory, which causes us to behave differently when we are stressed or depressed.

The key element of this research is manipulating the connectivity of the prefrontal cortex, for which there is further evidence that reinforces the idea that this could be crucial to treating depression. Transcranial direct current stimulation, which manipulates the brain in a similar way, is already being trialled as a treatment for depression, with results showing some evidence of a positive effect for sufferers.

Since this study concurs with what we know about mood disorders, this could certainly open up new avenues for treatment. Exploring these new causal links between stress, the brain’s neural connectivity and depression might make it possible to tweak brain circuitry in order to reverse whole mood disorders – at least in mice, to begin with.

The team’s findings not only help us to understand depression and other psychiatric illnesses, but also provide a powerful impetus toward developing treatments. Having a distinct “signature” of the mental disorder in question could be extremely useful as a reference point for new clinical treatments, and such a “screen” would facilitate more rapid and cost-effective testing of novel methods, encouraging more innovation and investment in these neglected areas.

https://www.weforum.org/agenda/2016/07/an-estimated-350m-people-suffer-from-depression-could-this-help-reverse-it