Physicists push new Parkinson’s treatment toward clinical trials

The most effective way to tackle debilitating diseases is to punch them at the start and keep them from growing.

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small “molecular tweezer” keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

“By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains,” she said. “In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson’s and other diseases that involve neurotoxic aggregation.”

Lapidus’ lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don’t know how they are built – a process known as folding.

Lapidus’ lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast.

Srabasti Acharya, lead author and doctoral candidate in Lapidus’ lab, tested the molecule, CLR01, which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It’s like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus’ research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren’t viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

It’s the BBB, in fact, that disproves the notion that people should simply eat more spicy food to stave off Parkinson’s disease.

Spicy misconceptions notwithstanding, CLR01 mimics curcumin molecules’ ability to prevent aggregation. But unlike the spice, CLR01 can crossover the BBB and treat its targeted site. Not only do they go to the right place, but CLR01 molecules also work even better because they speed up reconfiguration even more than curcumin. Additionally Acharya showed that CLR01 slows the first step of aggregation, and the results from the study map out a clear road map for moving the drug to clinical trials.

Hearing about a nontraditional physics lab that was advancing medicine is what brought Acharya to work with Lapidus.

“I knew I wanted to study physics when I came to MSU, but when I heard Dr. Lapidus’ presentation during orientation, I knew this is what I wanted to do,” Acharya said. “We are using physics to better understand biology to help cure actual diseases.”

To help move the research to the next phase, Gal Bitan, co-author and professor at UCLA, is using crowdsourcing to raise funds for the clinical trials. Log on to the indiegogo.com website for more information.

(Image caption: Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer’s. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center.)

“Chaperone” Compounds Offer New Approach to Alzheimer’s Treatment

A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.

Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.

“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”

In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.

In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”

Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.

This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.

The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”

More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .

“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”

Mirror, mirror on the wall - who has the fairest ORGANS of them all? Smart surface reveals ‘your’ insides

Mirrors have existed for thousands of years but the looking glass has just been given a 21st century makeover.

A new digital mirror gives people X-ray vision to let them see their insides – complete with bones, organs and muscle on show.

The 3D art installation, called the ‘Primary Intimacy of Being,’ recreates what a body looks like inside and eerily tracks a person’s movements as if they are seeing themselves.

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Brain ‘Stones’ Found in Man with Celiac Disease

A young man in Brazil who suffered from throbbing headaches and vision problems for 10 years turned out to have stonelike buildups of calcium in his brain.

The stones were likely a rare complication of the man’s celiac disease, a digestive condition that the man didn’t know he had, according to a new report of his case.

Because of his recurring headaches and vision problems, the man had been treated for migraines, but he hadn’t improved. When doctors did a CT scan, they found patches of calcification in the back of the man’s brain, in the areas that handle vision.

Lab tests showed that although the fluid circulating in the man’s brain was normal, it had higher levels of the antibodies linked to celiac disease, according to the report published in the New England Journal of Medicine.

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Smoking’s toll on mentally ill analyzed

Those in the United States with a mental illness diagnosis are much more likely to smoke cigarettes and smoke more heavily, and are less likely to quit smoking than those without mental illness, regardless of their specific diagnosis, a new study by researchers from the Yale School of Medicine shows.

They also found variations in smoking rates and likelihood of quitting among different diagnoses of mental illness. The results are reported in the April issue of the journal Tobacco Control.

Thirty-nine percent of adults with a psychiatric diagnosis smoked compared to 16% without a diagnosis, according to data from the National Epidemiologic Survey on Alcohol and Related Conditions analyzed by researchers. Two out of every three people with drug use disorder smoke, compared to one out of three with social phobia.

“We know that smokers with mental illness are more susceptible to smoking-related disease, and those with mental illness die 25 years earlier than adults without mental illness,” said Sherry McKee, associate professor of psychiatry, and senior author on the study. “Effective smoking cessation treatments are available and we know that smokers with mental illness can quit smoking. We need to address why smokers with mental illness are not being treated for their smoking.”

Over the three-year study period, 22% of smokers with no psychiatric disorders were able to quit smoking, whereas rates of quitting among those with psychiatric disorders were 25% lower. Rates of quitting were lowest among those with dysthymia (10%), agoraphobia (13%), and social phobia (13%). “We also found that individuals with multiple diagnoses had the lowest quit rates,” added Philip Smith, lead author on the study.

This study adds to evidence that smokers with mental illness consume nearly half of all cigarettes in the United States, despite making up a substantially smaller proportion of the population.

Researchers and policymakers are increasingly calling attention to this important public health issue, and this study helps point to a need for interventions and policy that directly help individuals with mental illness quit smoking.

Discovery Could Lead to Novel Therapies for Fragile X Syndrome

Scientists studying the most common form of inherited mental disability—a genetic disease called “Fragile X syndrome”—have uncovered new details about the cellular processes responsible for the condition that could lead to the development of therapies to restore some of the capabilities lost in affected individuals.

In a paper that will be published in the May 8 Molecular Cell, but is being made available this week in the early online edition of the journal, the researchers show how the fragile X mental retardation protein, or FMRP, which is in short supply in individuals with Fragile X, affects the protein-making structures of cells in the brain to cause the disease.

Researchers previously knew that in the absence of FMRP, protein-synthesizing structures called ribosomes translated some of the genetic instructions to produce proteins in the brain incorrectly, but exactly how this translation went awry was a mystery.

“The precise mechanism used by FMRP to regulate translation was not known,” said Simpson Joseph, a professor of chemistry and biochemistry at UC San Diego and a senior author of the study, which also involved scientists at the State University of New York at Albany and the New York State Department of Health. “Our study shows that FMRP can bind directly to the ribosome to regulate its function.”

More precisely, the researchers found that the protein binds to a region of the ribosome—between two ribosomal subunits—likely to be critical for the proper production of many proteins in the brain responsible for normal cognitive function. Using laboratory fruit flies, which have FMRP and ribosomes similar to those in humans, the scientists mapped the primary binding site of FMRP on the ribosome. With that information, medical researchers might be able to identify potential drugs that target those areas of the ribosome to help restore normal protein production in individuals with Fragile X.

“Similar to FMRP, it is possible that there are other proteins in the cell that bind directly to the ribosome as well to regulate gene expression,” said Joseph.

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Mutant Protein in Muscle Linked to Neuromuscular Disorder
A new therapeutic target for Kennedy’s disease and a potential treatment

Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.

But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.

SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington’s disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.

In the new paper, a team led by principal investigator Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein’s influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.   

In a related paper, published in the April 16, 2014 online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.

The scientists developed antisense oligonucleotides – sequences of synthesized genetic material – that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a MD-PhD student.

La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival. 

“The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA – at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people,” La Spada said.

Pictured: striated human skeletal muscle.