Major pathway identified in nerve cell death offers hope for therapies

Axon degeneration (top), caused by nerve injury or disease, depletes the energy supply within axons, shutting down communication between nerve cells. Washington University scientists blocked axon degeneration by supplementing neurons with a chemical called nicotinamide riboside, which kept the axons energized and healthy (bottom). Credit: Milbrandt lab

New research highlights how nerves - whether harmed by disease or traumatic injury - start to die, a discovery that unveils novel targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS).

27 april 2015--Peripheral neuropathy damages nerves in the body's extremities and can cause unrelenting pain, stinging, burning, itching and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.

The research, by scientists at Washington University School of Medicine in St. Louis, is reported online April 23 in the journal Science.

Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement and language.

As part of the study, the researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons.

"We have uncovered new details that let us piece together a major pathway involved in axon degeneration," said senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. "This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions."

A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another. Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.

Working in cell cultures, fruit flies and mice, Milbrandt and co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, and their colleagues showed that a protein already known to be involved in axon degeneration, acts like a switch to trigger axon degeneration after an injury.

M.D./Ph.D. student Josiah Gerdts (left) and Jeffrey Milbrandt, M.D., Ph.D., head of the Department of Genetics at Washington University School of Medicine, have identified a major pathway in the death of nerve axons, which carry messages between nerve cells. The finding provides a foundation for developing treatments against neurodegenerative diseases and peripheral neuropathies. Credit: Robert Boston, Washington University

Moreover, they found that this protein, once unleashed, causes a rapid decline in the energy supply within axons. Within minutes after the protein - called SARM1 - is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell's energy production, occurs within the axon.

"When a nerve is diseased or injured, SARM1 becomes more active, initiating a series of events that quickly causes an energetic catastrophe within the axon, and the axon undergoes self-destruction," said first author Josiah Gerdts, an MD/PhD student in Milbrandt's laboratory.

Working in neurons in which SARM1 was activated, the researchers showed they could completely block axon degeneration and neuron cell death by supplementing the cells with a precursor to NAD, a chemical called nicotinamide riboside. The neurons were able to use nicotinamide riboside to keep the axons energized and healthy.

Nicotinamide riboside has been linked in animal studies to good health and longevity, but its benefits have not been shown in people. The researchers said much more research is needed to know whether the chemical could slow or halt axon degeneration in the body.

"We are encouraged by the findings and think that identifying a class of drugs that block SARM1 activity has therapeutic potential in neurological disorders," Milbrandt said. "The molecular details this pathway provides give us a number of therapeutic avenues to attack."

More information: Gerdts J, Brace EJ, Sasaki Y, DiAntonio A and Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science. April 24, 2015. www.sciencemag.org/lookup/doi/… 1126/science.1258366

Provided by Washington University School of Medicine

New pathway is a common thread in age-related neurodegenerative diseases

LA JOLLA, CA, 31 jan 2009—How are neurodegenerative diseases such as Alzheimer's initiated, and why is age the major risk factor? A recent study of a protein called MOCA (Modifier of Cell Adhesion), carried out at the Salk Institute for Biological Studies, provides new clues to the answers of these fundamental questions.

Under normal circumstances, MOCA is a key member of the squadron charged with keeping Alzheimer's disease at bay. A team of researchers led by Salk professor David Schubert, Ph.D., demonstrated what happens when MOCA goes on furlough. In the process Schubert identified a novel pathway with broad implications for both Alzheimer's and other age-related neurodegenerative diseases.

Their findings, reported in the current issue of the Journal of Neuroscience, show how neurodegenerative disease starts, initiating in the nerve ending and inducing gradual changes, like a chain reaction over a long time. The animal model used in the study also will allow scientists to better understand the processes behind the formation of the protein aggregates that are common to most neurodegenerative diseases. In addition, it will provide new opportunities to target the earliest steps for therapy.

MOCA was initially identified as a protein that binds to presenilin, a molecule that when mutated causes familial Alzheimer's disease. MOCA is only found in neurons and regulates the expression of the beta amyloid protein responsible for the Alzheimer's plaques that are the hallmark of the disease. To better understand MOCA's function, Qi Chen, Ph.D., a senior scientist in Schubert's laboratory, created a line of mice genetically engineered to lack the gene for MOCA.

"Because of the initial studies in cultured cells that we had done, we expected these mice to develop plaques," explains Schubert. "What we found was that they develop ataxia—a motor coordination problem—as they age." Chen then studied the pathology of these mice and found that it reflected a common feature of most age-related neurological diseases, not just Alzheimer's.

The main problem turned out to be the degeneration of axons, the long projections that conduct impulses away from neurons. The axonal degeneration was caused by the accumulation of protein aggregates. Although the mice were not born with the problem, they acquired it, along with the ataxia, as they aged, and the ataxia worsened over time.

The aggregates started out small, initially causing few or no symptoms, but as they built up in the axons, they began to destroy the cytoskeleton, the internal framework of the cells, increasingly interfering with the transmission of signals from the nerve cells. Eventually the affected axons died, followed by the death of the nerve cell itself.

"Protein aggregates are common features of most age-related neurological diseases," says Chen, the first author of the study. "So is axon degeneration; we see it in Alzheimer's, ALS, and Huntington's disease. Motor problems such as ataxia may be the most obvious manifestation because the aggregates appear in the long axons of the spinal cord. But the axonal aggregates also appear in the brain and may be the first step in the events that lead to age-associated neurological disease."

After documenting the sequence of physiological and behavioral events that characterize the axon degeneration, Chen then sought to piece together the molecular pathway behind it, starting with MOCA and connecting findings from disparate studies that previously had identified parts of the pathway. He ended up with a single, step-by-step process for axon degeneration that for the first time linked together a number of diseases and conditions, including a form of mental retardation in humans.

"We had known that MOCA affected the cytoskeleton for some time, but no one had put together clear evidence showing how the sequential age-associated changes in the cytoskeleton of the nerve take place. Dr. Chen was able to do this, thereby connecting the disease pathology with the molecular biology," says Schubert. "Now we know that MOCA is essential to the functional integrity of axons and have defined a complete pathway for axon degeneration."

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The study was funded with support from the National Institutes of Health, the Bundy Foundation, the Alzheimer's Association, and the Shirley Foundation for Alzheimer's Research.

Sniff Test May Signal Disorders’ Early Stages

By ELIZABETH SVOBODA

Seven years ago, Robert Gesteland, a biologist at the University of Cincinnati, and his colleague Robert Frank, a psychologist, decided to tackle a perplexing topic: why some people are more open to trying unfamiliar foods. Suspecting that picky eaters might be more attuned to strong smells, they set about trying to quantify this.
“Someone turned up the suggestion that people might take smaller sniffs once they detect a smell,” Dr. Gesteland said. “It was natural for me to say, ‘How can we measure that? Let me see what I can put together in the garage.’ ”
Since then, the apparatus he built at his home workbench has evolved into a device called the Sniff Magnitude Test — and one the two scientists are using for a much different purpose. As the only test that measures patients’ ability to smell without requiring them to put the sensation into words, it shows promise in helping detect neurodegenerative disorders like Alzheimer’s and Parkinson’s in their earliest stages.
Doctors have known for years that when people with these diseases begin the slide toward dementia, an inability to smell is often the first sign of a problem. Because comparatively few brain cells are devoted to processing odors, “there’s good reason to think the olfactory system is affected very early on with these conditions,” said Richard Doty, director of the University of Pennsylvania’s Smell and Taste Center, who has done research comparing the Sniff Magnitude Test with other smell-assessment measures. “Many patients tell their doctors they can’t smell years before they actually get Alzheimer’s or Parkinson’s.”
The Sniff Magnitude Test, developed with the aid of a $1.3 million grant from the National Institutes of Health, consists of a nasal tube called a cannula attached to a plastic container about the size and shape of a coffee thermos. Chemical vapors inside the canister are released through the tube, exposing subjects to a series of smells, some more objectionable than others.
“People describe some of the smells as skunky or sewerlike,” said Jason Bailie, a University of Cincinnati graduate student working on the test. “There’s also one that smells like banana.”
As patients take whiffs of each new fragrance, sensors in the thermos unit measure the negative pressure the inhalations produce. The size and intensity of these sniffs turn out to be important gauges of olfactory ability. After detecting a strong or disagreeable odor, people with a normal sense of smell take very small sniffs to avoid smelling it. Subjects with an impaired sense of smell, on the other hand, continue taking deep whiffs, because the scent does not register in their brains.
In a study published last year in the journal Otolaryngology, Dr. Frank and Dr. Gesteland reported a high degree of correlation between patients’ scores on the Sniff Magnitude Test and their scores on older smell-assessment tests. The WR Medical Electronics Company in Stillwater, Minn., has started making the device, hoping to begin distribution in the next year.
It will enter a crowded field. Many tests to gauge smelling ability are already available to doctors, including the current gold standard, the University of Pennsylvania Smell Identification Test, which Dr. Doty developed in the 1980s. This test presents patients with 40 squares of paper infused with odors and asks them to choose an accurate description of each smell from four options. Similar tests include the Connecticut Chemosensory Clinical Research Center Test and the “Sniffin’ Sticks” test, which dispenses odors from penlike devices.
But those tests generally ask subjects to relate odors to presumably familiar smells like “dill pickle,” “root beer” and “pumpkin pie,” which may be a challenge for people from other cultures or those whose cognitive abilities are slipping. The Sniff Magnitude Test does not require these kinds of subjective comparisons.
The Cincinnati team’s efforts have piqued the interest of other researchers, including Dr. Doty and Alan Hirsch of the Smell and Taste Research and Treatment Foundation, who is using the Sniff test in his clinical practice. “They’ve chosen some very good odors that stimulate the olfactory system effectively,” Dr. Doty said. “This is a very novel approach — it just needs to be tested more broadly.”
Still, Dr. Doty added, the Sniff Magnitude Test may not be the ideal way to assess every patient with cognitive deficits. “Very early in life, we make a connection between an odor and its source,” he said. “We give it a name. If the connection between the name of an odor and the odor itself is what’s breaking down in an Alzheimer’s patient, this test might not be as helpful,” because it does not tell evaluators how a patient identifies and categorizes smells. The Sniff Magnitude Test is likely to raise red flags only if an impending cognitive disorder directly affects a patient’s olfactory abilities.
Even for patients who fall into this category, the test is no diagnostic panacea. Dr. Gesteland cautions that it should not be used by itself, but in conjunction with more traditional neurological assessments. A poor test result in an older person does not necessarily indicate the presence of Alzheimer’s or Parkinson’s, but it does alert doctors that further investigation is necessary.
“As people get older, their sense of smell can diminish independent of any dementia,” Dr. Gesteland said. “If a patient does poorly, you have to figure out whether the problem is with the nose, with the nerve fibers that go from the nose to the brain, or with how the central nervous system interprets that message.”
Beyond its usefulness as a first-alert mechanism, Dr. Frank thinks the test will help doctors zero in on specific diagnoses. Parkinson’s, for instance, has a clinical profile similar to a condition called progressive supranuclear palsy, but the palsy disorder seldom affects the ability to smell. The test should also help distinguish Parkinson’s and Alzheimer’s from major depression in the elderly, because depressed patients do not experience sensory deficits.
In his most ambitious moments, Dr. Frank envisions doctors administering the Sniff test across the board as patients enter their 50s and 60s. “If folks take this test and some of them don’t do very well,” Dr. Frank said, “we need to be able to refer them.”