Gene Involved in Neurodegeneration Keeps Clock Running

Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.

In a study of the common fruit fly, the researchers found the gene, called Ataxin-2, keeps the clock responsible for sleeping and waking on a 24-hour rhythm. Without the gene, the rhythm of the fruit fly’s sleep-wake cycle is disturbed, making waking up on a regular schedule difficult for the fly.

The discovery is particularly interesting because mutations in the human Ataxin-2 gene are known to cause a rare disorder called spinocerebellar ataxia (SCA) and also contribute to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with SCA suffer from sleep abnormalities before other symptoms of the disease appear.

This study linking the Ataxin-2 gene with abnormalities in the sleep-wake cycle could help pinpoint what is causing these neurodegenerative diseases as well as provide a deeper understanding of the human sleep-wake cycle.

The findings will be published May 17 in the journal Science. Ravi Allada, M.D., professor of neurobiology in the Weinberg College of Arts and Sciences, and Chunghun Lim, a postdoctoral fellow in his lab, are authors of the paper.

Period (per) is a well-studied gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Allada and Lim discovered that Ataxin-2 helps activate translation of PER RNA into PER protein, a key step in making the circadian clock run properly.

“It’s possible that Ataxin-2’s function as an activator of protein translation may be central to understanding how, when you mutate the gene and disrupt its function, it may be causing or contributing to diseases such as ALS or spinocerebellar ataxia,” Allada said.

The fruit fly Drosophila melanogaster is a model organism for scientists studying the sleep-wake cycle because the fly’s genes are highly conserved with the genes of humans.

“I like to say that flies sleep similarly to humans, except flies don’t use pillows,” said Allada, who also is associate director for Northwestern’s Center for Sleep and Circadian Biology. The biological timing mechanism for all animals comes from a common ancestor hundreds of millions of years ago.

Ataxin-2 is the second gene in a little more than two years that Northwestern researchers have identified as a core gear of the circadian clock, and the two genes play similar roles.

Allada, Lim and colleagues in 2011 reported their discovery of a gene, which they dubbed “twenty-four,” that plays a role in translating the PER protein, keeping the sleep-wake cycle on a 24-hour rhythm.

Allada and Lim wanted to better understand how twenty-four works, so they looked at proteins that associate with twenty-four. They found the twenty-four protein sticking to ATAXIN-2 and decided to investigate further. In their experiments, reported in Science, Allada and Lim discovered the Ataxin-2 and twenty-four genes appear to be partners in PER protein translation.

“We’ve really started to define a pathway that regulates the circadian clock and seems to be especially important in a specific group of neurons that governs the fly’s morning wake-up,” Allada said. “We saw that the molecular and behavioral consequences of losing Ataxin-2 are nearly the same as losing twenty-four.”

As is the case in a mutation of the twenty-four gene, when the Ataxin-2 gene is not present, very little PER protein is found in the circadian pacemaker neurons of the brain, and the fly’s sleep-wake rhythm is disturbed.

Boosting ‘cellular garbage disposal’ can delay the aging process

UCLA life scientists have identified a gene previously implicated in Parkinson’s disease that can delay the onset of aging and extend the healthy life span of fruit flies. The research, they say, could have important implications for aging and disease in humans.

The gene, called parkin, serves at least two vital functions: It marks damaged proteins so that cells can discard them before they become toxic, and it is believed to play a key role in the removal of damaged mitochondria from cells.

"Aging is a major risk factor for the development and progression of many neurodegenerative diseases," said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research. "We think that our findings shed light on the molecular mechanisms that connect these processes."

In the research, published today in the early online edition of the journal Proceedings of the National Academy of Sciences, Walker and his colleagues show that parkin can modulate the aging process in fruit flies, which typically live less than two months. The researchers increased parkin levels in the cells of the flies and found that this extended their life span by more than 25 percent, compared with a control group that did not receive additional parkin.

"In the control group, the flies are all dead by Day 50," Walker said. "In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

"Just by increasing the levels of parkin, they live substantially longer while remaining healthy, active and fertile," said Anil Rana, a postdoctoral scholar in Walker’s laboratory and lead author of the research. "That is what we want to achieve in aging research — not only to increase their life span but to increase their health span as well."

Treatments to increase parkin expression may delay the onset and progression of Parkinson’s disease and other age-related diseases, the biologists believe. (If parkin sounds related to Parkinson’s, it is. While the vast majority of people with the disease get it in older age, some who are born with a mutation in the parkin gene develop early-onset, Parkinson’s-like symptoms.)

"Our research may be telling us that parkin could be an important therapeutic target for neurodegenerative diseases and perhaps other diseases of aging," Walker said. "Instead of studying the diseases of aging one by one — Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes — we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it can, of course, take many years, but that is our goal."

'The garbage men in our cells go on strike'

To function properly, proteins must fold correctly, and they fold in complex ways. As we age, our cells accumulate damaged or misfolded proteins. When proteins fold incorrectly, the cellular machinery can sometimes repair them. When it cannot, parkin enables cells to discard the damaged proteins, said Walker, a member of UCLA’s Molecular Biology Institute.

"If a protein is damaged beyond repair, the cell can recognize that and eliminate the protein before it becomes toxic," he said. "Think of it like a cellular garbage disposal. Parkin helps to mark damaged proteins for disposal. It’s like parkin places a sticker on the damaged protein that says ‘Degrade Me,’ and then the cell gets rid of this protein. That process seems to decline with age. As we get older, the garbage men in our cells go on strike. Overexpressed parkin seems to tell them to get back to work."

Rana focused on the effects of increased parkin activity at the cellular and tissue levels. Do flies with increased parkin show fewer damaged proteins at an advanced age? “The remarkable finding is yes, indeed,” Walker said.

Parkin has recently been shown to perform a similarly important function with regard to mitochondria, the tiny power generators in cells that control cell growth and tell cells when to live and die. Mitochandria become less efficient and less active as we age, and the loss of mitochondrial activity has been implicated in Alzheimer’s, Parkinson’s and other neurodegenerative diseases, as well as in the aging process, Walker said.

Parkin appears to degrade the damaged mitochondria, perhaps by marking or changing their outer membrane structure, in effect telling the cell, “This is damaged and potentially toxic. Get rid of it.”

If parkin is good, is more parkin even better?

While the researchers found that increased parkin can extend the life of fruit flies, Rana also discovered that too much parkin can have the opposite effect — it becomes toxic to the flies. When he quadrupled the normal amount of parkin, the fruit flies lived substantially longer, but when he increased the amount by a factor of 30, the flies died sooner.

"If you bombard the cell with too much parkin, it could start eliminating healthy proteins," Rana said.

In the lower doses, however, the scientists found no adverse effects. Walker believes the fruit fly is a good model for studying aging in humans — who also have the parkin gene — because scientists know all of the fruit fly’s genes and can switch individual genes on and off.

Previous research has shown that fruit flies die sooner when you remove parkin, Walker noted.

Walker and Rana do not know what the optimal amount of parkin would be in humans.

While the biologists increased parkin activity in every cell in the fruit fly, Rana also conducted an experiment in which he increased parkin expression only in the nervous system. That, too, was sufficient to make the flies live longer.

"This tells us that parkin is neuroprotective during aging," Walker said. "However, the beneficial effects of parkin are greater — twice as large — when we increased its expression everywhere."

"We were excited about this research from the beginning but did not know then that the life span increase would be this impressive," Rana said.

The image that accompanies this news release shows clumps or aggregates of damaged proteins in an aged brain from a normal fly (left panel) and an age-matched brain with increased neuronal parkin levels (right panel). As can be seen, increasing parkin levels in the aging brain reduces the accumulation of aggregated proteins.

Scientists have found that this kind of protein aggregation occurs in mammals as well, including humans, Rana said.

"Imagine the damage the accumulation of protein trash is doing to the cell," Walker said. "With increased Parkin, the trash has been collected. Without it, the garbage that should be discarded is accumulating in the cells."

Blind and yet not blind

If a mosquito approaches a human ear or a bee heads for the next flower, two things are important: the insects must be able to locate their destination and correct course deviations, caused by a gust of wind for example. How does the brain process these different situations so that both behaviours are possible? Scientists at the Max Planck Institute of Neurobiology in Martinsried have demonstrated in behavioural experiments that both behaviours are controlled by separate circuits in the brain of the fruit fly (Drosophila). One of these neural networks processes motion information in the surrounding environment and helps the fly to stabilise its course. The other is responsible for determining the position of an object and is used for object fixation.

If a drum with vertical stripes rotates around an insect, the animal will rotate in the same direction as the stripes. This innate behaviour is known as an optomotor reaction. The experiment replicates a natural phenomenon: if, for example, a gust of wind moves a flying fly to the right, from the fly’s perspective, the surroundings move to the left by its eyes. The optomotor reaction consequently leads to a compensation for the gust of wind and brings the fly back on course. Scientists have long suspected that the nerve cells controlling this behaviour are located in the lobula plate of the fly’s brain. Up until now, however, it was not clear whether these cells are necessary to control the observed behaviour.

Alexander Borst and his department at the Max Planck Institute of Neurobiology are investigating how motion information is processed in the brain of the fly. To find out whether the lobula plate plays a role in the optomotor reaction, the neurobiologists developed a behavioural testing apparatus: in a virtual environment, they presented flies with a rotating striped pattern to which the flies displayed a clear optomotor reaction. However, when the scientists blocked the nerve cells from which the lobula plate receives its information, the behaviours disappeared completely. The flies were thus motion-blind. The experiments show that the lobula plate is a necessary element in stabilising the course of the fly.

In nature, however, flies must also be able to process information about other things than motion. Was this still possible? The next thing that the neurobiologists concentrated on was another, well-documented behaviour of insects: object fixation. If a single vertical stripe is displayed during the experiment, flies will turn to the stripe and try to keep it in front of them. This object fixation enables the animals to approach an object or to “keep an eye” on it. In the experiment, the scientists allowed a vertical stripe to appear slowly at different locations in the flies’ field of vision and then disappear again. If the stripe appeared on the right side of the fly, the animals turned to the right, if it appeared on the left, they turned to the left. If the motion perception system controls this behaviour, then motion-blind animals should no longer be able locate the stripes. Interestingly, motion-blind flies and control flies responded in exactly the same way.

The scientists concluded from these experiments that an independent position perception system must co-exist with the motion perception system. If a small object moves in the space, local changes in brightness occur. These are recorded by the position perception system. Motion-blind flies can therefore still recognise the position of an object even if they can no longer see it moving.

“It was a very complicated process to set up the experiment in a way that solid results could be obtained,” explains Armin Bahl, the lead author of the study. It was previously assumed that cells in the lobula plate are responsible for motion perception, as well as for object fixation. The scientists have now refuted this assumption and already described important properties of the fixation behaviour. “We do not yet know exactly where the cells of the position perception system are located in the fly’s brain, but we have a few good candidates,” says Armin Bahl, indicating the direction that the research will now take.

Unusual comparison nets new sleep loss marker

For years, Paul Shaw, PhD, a researcher at Washington University School of Medicine in St. Louis, has used what he learns in fruit flies to look for markers of sleep loss in humans.

Shaw reverses the process in a new paper, taking what he finds in humans back to the flies and gaining new insight into humans as a result: identification of a human gene that is more active after sleep deprivation.

“I’m calling the approach cross-translational research,” says Shaw, associate professor of neurobiology. “Normally we go from model to human, but there’s no reason why we can’t take our studies from human to model and back again.”

Shaw and his colleagues plan to use the information they are gaining to create a panel of tests for sleep loss. The tests may one day help assess a person’s risk of falling asleep at the wheel of a car or in other dangerous contexts.

PLOS One published the results on April 24.

Scientists have known for years that sleep disorders and disruption raise blood serum levels of interleukin 6, an inflammatory immune compound. Shaw showed that this change is also detectable in saliva samples from sleep-deprived rats and humans.

Based on this link, Shaw tested the activity of other immune proteins in humans to see if any changed after sleep loss. The scientists took saliva samples from research participants after they had a normal night’s sleep and after they stayed awake for 30 hours. They found two immune genes whose activity levels rose during sleep deprivation.

“Normally we would do additional human experiments to verify these links,” Shaw says. “But those studies can be quite expensive, so we thought we’d test the connections in flies first.”

The researchers identified genes in the fruit fly that were equivalent to the human genes, but their activity didn’t increase when flies lost sleep. When they screened other, similar fruit fly genes, though, the scientists found one that did.

“We’ve seen this kind of switch happen before as we compared families of fly genes and families of human genes,” Shaw says. “Sometimes the gene performing a particular role will change, but the task will still be handled by a gene in the same family.”

When the scientists looked for the human version of the newly identified fly marker for sleep deprivation, they found ITGA5 and realized it hadn’t been among the human immune genes they screened at the start of the study. Testing ITGA5 activity in the saliva samples revealed that its activity levels increased during sleep deprivation.

“We will need more time to figure out how useful this particular marker will be for detecting sleep deprivation in humans,” Shaw says. “In the meantime, we’re going to continue jumping between our flies and humans to maximize our insights.”

Fight Control: Researchers link individual neurons to regulation of aggressive behavior in flies

Scientists have long pondered the roots of aggression—and ways to temper it. Now, new research is beginning to illuminate the cellular-level circuitry responsible for modulating aggression in fruit flies, with the hope of someday translating the findings to humans.

Researchers at Harvard Medical School have identified two pairs of dopamine-producing neurons, also called dopaminergic neurons, and traced their aggression-modulating action to a common structure in the fly brain called the central complex, suggesting that important components of aggression-related behaviors may be processed there.

“This is the first research to identify single dopaminergic neurons that modulate a complex behavior—aggression—in fruit flies,” said Edward Kravitz, George Packer Berry Professor of Neurobiology at HMS and lead author of the study.

“We don’t know how complex this modulatory circuit is, but we now have a key element of it. If we eliminate or increase the function of that dopaminergic neuron, it affects the circuit of the brain responsible for controlling aggression,” Kravitz said.

The findings were published last week in PNAS.

Flies are an ideal animal model for neurological research because genetic methods allow scientists to manipulate neurons and simultaneously observe the resulting behaviors. Many fundamental nervous system mechanisms in flies are similar to those in humans. In fact, both flies and humans share the same neurohormones.

Dopamine is one such neurohormone, and across species it affects a range of behaviors, from learning and memory to motivation and movement. In humans, neurohormones are associated with conditions such as Parkinson’s disease and psychiatric disorders.

Dopaminergic neurons are found in small numbers in particular parts of nervous systems. In humans, there are about 200,000 to 400,000 of these neurons; in fruit flies there are about 100. While their numbers are few, these neurons influence a vast array of behaviors.

Kravitz, along with Olga Alekseyenko, a postdoctoral fellow in the Kravitz lab and first author on the paper, set out to discover how these few dopaminergic neurons can influence such a wide range of behaviors.

To do this, study co-first author, Yick-Bun Chan, HMS research associate in neurobiology, genetically engineered 200 lines of fruit flies. He then used them to target select dopaminergic neurons that could be activated or silenced while the flies engaged in various behaviors.

The team detected two pairs of dopaminergic neurons that affected aggressive behavior in the flies. Interestingly, aggression was increased in the flies either by augmenting the function of these cells or by deactivating them.

In fruit flies, males fight for territory and form stable hierarchical relationships. Using previous observations and analysis of more than 20,000 interactions in fly fights, the team established quantitative measures of aggressive behavior, such as lunging, that allowed them to compare aggression levels in different fly attacks.

“When we turned off the pairs of dopaminergic neurons, the flies fought with more lunging; when we turned them on, they also fought at higher intensity levels. Apparently normal levels of aggression require a precise amount of dopamine released at a specific time and place in the nervous system. These results suggest that these neurons ordinarily hold aggression in check,” said Alekseyenko.

Also significant was the finding that while the two sets of dopaminergic neurons modulated aggression, they did not influence other behaviors.

The first pair of neurons are found in the PPM3 cluster of neurons in the fly brain and the second are within the T1 cluster. Both pairs innervate different parts of the central complex, an important structure in the fly brain.

“We already knew that dopamine receptors are present in the central complex, but we didn’t know which dopamine neurons connected to the receptors or what behaviors those neurons affected,” said Alekseyenko.

“Now we know that two pairs of aggression-mediating dopaminergic neurons terminate in different regions of the central complex, and we know that those regions have different types of dopamine receptors. Our study shows that aggression is one of the behaviors coordinated in these regions of the brain, but we still don’t fully understand the process,” he said.

In a third group of flies, a neuron pair that projected into a different part of the brain was identified. These neurons affected locomotion and sleep, but did not influence aggression.

Kravitz said the next phase of the research will be to use genetic tools to allow his team to identify the subsequent steps in the brain circuitry—which neurons are pre- and post-synaptic to the T1 and PPM3 neurons and how that affects neuronal network function.

The goal will be to establish fundamental principles for how dopaminergic neurons work in the fruit fly system, with the hope that the research will one day translate to how these neurons work in higher species. This may ultimately aid in the development of new dopamine-targeted medications for humans.

“We can now relate these two pairs of neurons specifically to one behavior, and that is aggression,” Kravitz said. “That means we have one piece of the puzzle.”

'Strikingly similar' brains of man and fly may aid mental health research

A new study by scientists at King’s College London’s Institute of Psychiatry and the University of Arizona (UA) published in Science reveals the deep similarities in how the brain regulates behaviour in arthropods (such as flies and crabs) and vertebrates (such as fish, mice and humans).

The findings shed new light on the evolution of the brain and behaviour and may aid understanding of disease mechanisms underlying mental health problems.

Based on their own findings and available literature, Dr Frank Hirth (King’s) and Dr Nicholas Strausfeld (UA) compared the development and function of the central brain regions in arthropods (the ‘central complex’) and vertebrates (the ‘basal ganglia’).

Research suggests that both brain structures derive from embryonic stem cells at the base of the developing forebrain and that, despite the major differences between species, their respective constitutions and specifications derive from similar genetic programmes.

The authors describe that nerve cells in the central complex and the basal ganglia become inter-connected and communicate with each other in similar ways, facilitating the regulation of adaptive behaviours. In other words, the response of a fly or a mouse to internal stimuli such as hunger or sleep, and external stimuli such as light/dark or temperature, are regulated by similar neural mechanisms.

Dr Hirth from the Department of Neuroscience at King’s Institute of Psychiatry says: “Flies, crabs, mice, humans: all experience hunger, need sleep and have a preference for a comfortable temperature so we speculated there must be a similar mechanism regulating these behaviours. We were amazed to find just how deep the similarities go, despite the differences in size and appearance of these species and their brains.”

Dr Strausfeld, a Regents Professor in the UA’s Department of Neuroscience and the Director of the UA’s Center for Insect Science, says: “When you compare the two structures, you find that they are very similar in terms of how they’re organized. Their development is orchestrated by a whole suite of genes that are homologous between flies and mice, and the behavioral deficits resulting from disturbances in the two systems are remarkably similar as well.”

In humans, dysfunction of the basal ganglia can cause severe mental health problems ranging from autism, schizophrenia and psychosis, to neurodegeneration - as seen in Parkinson’s disease, motor neurone disease and dementia - as well as sleep disturbances, attention deficits and memory impairment. Similarly, when parts of the central complex are affected in fruit flies, they display similar impairments.

Dr Hirth (King’s) adds: “The deep similarities we see between how our brains and those of insects regulate behaviour suggest a common evolutionary origin. It means that prototype brain circuits, essential for behavioural choice, originated very early and have been maintained across animal species throughout evolutionary time. As surprising as it may seem, from insects’ dysfunctional brains, we can learn a great deal about how human brain disorders come about.”

The findings suggest that arthropod and vertebrate brain circuitries derive from a common ancestor already possessing a complex neural structure mediating the selection and maintenance of behavioural actions.

Although no fossil remains of the common ancestor exist, trace fossils, in the form of tracks criss-crossing the seafloor hundreds of millions of years ago, reveal purposeful changes in direction.

Dr Strausfeld (UA) says: “If you compare these tracks to the tracks left behind by a foraging fly larva on an agar plate or the tunnels made by a leaf-mining insect, they’re very similar. They all suggest that the animal chose to perform various different actions, and action selection is precisely what the central complex and the basal ganglia do.”

The trace fossils may thus support the early existence of brains complex enough to allow for action selection and a shared ancestry of neural structures between invertebrates and vertebrates.

Flies reveal that a sense of smell, like a melody, depends upon timing

The sense of smell remains a mystery in many respects. Fragrance companies, for instance, know it is crucial that chemical compounds in perfumes reach nostrils at different rates to create the desired sensory experience, but it is has been unclear why. Yale researchers decided to interrogate the common fruit fly for answers.

The team of Yale scientist Thierry Emonet, his postdoctoral associate Carlotta Martelli, and his colleague John Carlson systematically recorded both the stimulus reaching the fly and the responses of individual neurons over time. They found that the timing of neuronal response was independent of the concentration of the odor in the air, which in theory might help flies track fluctuating odor stimuli. However, the timing of neuronal response did depend on the identity of the odor.

Different odors elicited tiny delays in neural response. Such odor-dependent delays could be useful to the brain processing complex scents, say the scientists. The research also shows that specific interactions between odors and surfaces can affect the timing of the stimulus and therefore neural response.

Emonet says the findings suggest the world of smell is like music, in which chemical compounds of the scent act as notes and enable recognition of specific odors depending upon when they are played, or processed. For more information on the research, see the April 9 issue of the journal Neuroscience.

Neuroscientists show ’jumping genes’ may contribute to aging-related brain defects

As the body ages, the physical effects are notable; wrinkles in the skin appear, physical exertion becomes harder. But there are also less visible processes going on. Inside aging brains there is another phenomenon at work, which may contribute to age-related brain defects.

In a paper published in the journal Nature Neuroscience CSHL Associate Professor Joshua Dubnau and colleagues show that so-called “jumping genes,” or transposons, increase in abundance and activity in the brains of fruit flies as they age.

Originally discovered at CSHL by Professor Barbara McClintock while working on maize (corn) in the 1940s, transposons are typically repeat DNA sequences that insert themselves into the DNA of an animal or plant.

The moniker “jumping genes” comes from the fact that when activated they can reinsert themselves, or transpose, into another part of the genome. In the course of doing so they are thought to either provide variations in genetic function or, especially in the germline, induce potentially fatal disruptive defects.

Jumping genes in the brains of fruit flies

The median lifespan of a fruit fly can be measured in days. The average fly lives for somewhere between 40-50 days. But they provide a powerful model with which to get at the genetics of things like aging and brain function, including memory.

Dubnau’s interest was piqued by an experiment in which his team showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory—which was tested using a trained Pavolvian response to smell. “This is a neurodegenerative defect that gets profoundly more apparent with age of the flies,” notes Dubnau.

Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, Dubnau and colleagues in his lab, including Wanhe Li and Lisa Prazak, were compelled to look for transposons.

Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development.

When Dubnau’s group looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome.

When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age. In fact the levels of transposons in young Ago2 “knock-out” flies were equivalent to those in much older normal flies, and increased further still as the Ago2 knock-out flies aged.

Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. “Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age,” Dubnau reports.

In a previous paper the Dubnau lab, in collaboration with CSHL Assistant Professor Molly Hammell, established a connection between transposons and devastating neurodegenerative diseases such ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) and FTLD (frontotemporal lobar degeneration). The link was the protein TDP-43, which they showed controls transposon activity.

Taken together with the results in his team’s new paper, Dubnau proposes that a “transposon storm” may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.

However, his studies so far don’t address whether transposons are the cause or an effect of aging-related brain defects. “The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration,” Dubnau says.

Flies Model a Potential Sweet Treatment for Parkinson’s disease

Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson’s disease (PD) using a common sweetener, mannitol. This research is presented today at the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., April 3-7, 2013.

Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the “manna” that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can’t. For most commercial uses it is extracted from seaweed although chemists can synthesize it. And it can be used for more than just a sweetener.

The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes.

Mannitol has another, less-explored talent: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.

Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson’s disease by getting into the brain and then restoring normal folding to α-synuclein.

Daniel Segal, PhD, and colleagues at Tel Aviv University investigated the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein.

The researchers used a “locomotion climbing assay” to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they can’t move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.

An experimental run tested flies daily for 27 days. After that time, 72% of normal flies climbed up, in comparison to 38% of the PD flies. Their lack of ascension up the sides of the test tube indicated “severe motor dysfunction.”

In contrast, were flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials. These flies fared much better — 70% of them could climb after 27 days. And slices of their brains revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.

It’s a long way from helping climbing-impaired flies to a new treatment for people, but the research suggests a possible novel therapeutic direction. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not chew a ton of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to improved climbing by flies, in which a rolling drum (“rotarod”) activity assesses mobility.

“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. A preliminary clinical trial of mannitol on a small number of volunteers might follow if results in mice support those seen in the flies, he added, but that is still many research steps away.

(Image: Wikimedia Commons)