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Doctors diagnose as many as 60,000 new cases of Parkinson's disease (PD) every year in the United States. Yet diagnosing PD with certainty can take years-long after early signs and symptoms have appeared.
The Israeli startup BioShai has a game-changing product on the horizon: PDx, the world's first simple blood test for the early diagnosis of PD.
The test results can be combined with clinical data, providing a more accurate diagnosis to help physicians decide on the best course of treatment at a much earlier stage.
More than 10 million people worldwide are living with this chronic and progressive movement disorder caused by the malfunction and death of neurons that produce dopamine, a chemical that coordinates the brain's control of movement and coordination.
In 1998, Andy Clark and David Chalmers proposed that a computer operates together with our brains as an “extended mind,” potentially offering additional processing capabilities as we work out problems, as well as an annex for our memories containing information, images, and so on. Now a professor of biomedical engineering at the University of Southern California, Theodore Berger, is working to bring to market human memory enhancement in the form of a prosthetic implanted in the brain. He’s already testing it attached to humans.
The prosthetic, which Berger has been working on for ten years, can function as an artificial hippocampus, the area in the brain associated with memory and spatial navigation.
The plan is for the device to convert short-term memory into long-term memory and potentially store it as the hippocampus does. His research has been encouraging so far.
Berger began by teaching a rabbit to associate an audio tone with a puff of air administered to the rabbit’s face, causing it to blink. Electrodes attached to the rabbit allowed Berger to observe patterns of activity firing off in the rabbit’s hippocampus. Berger refers to these patterns as a “space-time code” representing where the neurons are in the rabbit’s brain at a specific moment. Berger watched them evolving as the rabbit learned to associate the tone and puff of air. He told Wired, “As the space-time code propagates into the different layers of the hippocampus, it’s gradually changed into a different space-time code.” Eventually, the tone alone was enough for the hippocampus to produce a recallable space-time code based on the latest incoming version to make the rabbit blink.
The manner in which the hippocampus was processing the rabbit’s memory and producing a recallable space-time code became predictable enough to Berger that he was able to develop a mathematical model representing the process.
Berger then built an artificial rat hippocampus — his experimental prosthesis —to test his observations and model. By training rats to press a lever with electrodes monitoring their hippocampuses, Berger was able to acquire the corresponding space-time codes. Running that code through his mathematical model and sending it back to the rats’ brains, his system was validated as the rats successfully pressed their levers. “They recall the correct code as if they’ve created it themselves. Now we’re putting the memory back into the brain,” Berger reports.
It’s maybe the this last statement that’s so intriguing. Does the brain have some kind of master memory index? Has it somehow integrated the artificial hippocampus’s memories into the rats’ directory? Will it also happen in humans?
Dustin Tyler, a professor of engineering at Case Western Reserve University, cautioned Wired, “All of these prosthetics interfacing with the brain have one fundamental challenge. There are billions of neurons in the brain and trillions of connections between them that make them all work together. Trying to find technology that will go into that mass of neurons and be able to connect with them on a reasonably high-resolution level is tricky.”
Still, Bergen himself is optimistic, telling IEEE Spectrum, “We’re testing it in humans now, and getting good initial results. We’re going to go forward with the goal of commercializing this prosthesis.”
What he envisions bringing to market based on his research is a brain prosthetic for people with memory problems. The tiny device would be implanted in the patient’s own hippocampus from where it would stimulate the neurons responsible for turning short-term memories into long-term memories. He hopes it can help patients suffering from Alzheimer’s, other forms of dementia, stroke victims and people whose brains have been injured.
Berger’s business partner in this is tech entrepreneur Bryan Johnson. After selling his payment gateway Braintree to PayPal for $800, he started a venture capital fund, the OS Fund. Its web site states its mission: “The OS Fund invests in entrepreneurs working towards quantum-leap discoveries that promise to rewrite the operating systems of life.” Johnson sees Berger’s work as one such discovery, and formed kernel to support it, running the company himself with Berger as the company’s Chief Science Officer.
Rats and monkeys — the prosthetic improved the memories of rhesus monkeys attached to their prefrontal cortex — are one thing. The greater number of neurons in human brains is a big issue that needs to be grappled before Berger’s implant will work well for humans: It’s difficult to gain a comprehensive view of what’s going on with larger brains due to their greater number of neurons. (Rat brains have about 200 million neurons; humans have 86 billion.) Berger warns, “Our information will be biased based on the neurons we’re able to record from,” and he looks forward to tools that can capture broader swaths of data going forward. It’s anticipated that they’ll need to pack a greater number of electrodes into prostheses.
Human trials so far have been with in-patient epileptics with electrodes already in place for their epilepsy treatments. Berger’s team has observed and recorded activity in the hippocampus during memory tests, and they’ve been encouragingly successful at enhancing patients’ memories by stimulating neurons there. kernel will be funding additional human trials.
Summary: The same processes that regulate neural activity during sleep may also play a role in attention, researchers report.
Source: Stanford.
Understanding these newly discovered cycles requires knowing a bit about how the brain is organized. NeuroscienceNews.com image is in the public domain.
When we are in a deep slumber our brain’s activity ebbs and flows in big, obvious waves, like watching a tide of human bodies rise up and sit down around a sports stadium. It’s hard to miss.
Now, Stanford researchers have found, those same cycles exist in wake as in sleep, but with only small sections sitting and standing in unison rather than the entire stadium. It’s as if tiny portions of the brain are independently falling asleep and waking back up all the time.
What’s more, it appears that when the neurons have cycled into the more active, or “on,” state they are better at responding to the world. The neurons also spend more time in the on state when paying attention to a task. This finding suggests processes that regulate brain activity in sleep might also play a role in attention.
“Selective attention is similar to making small parts of your brain a little bit more awake,” said Tatiana Engel, a postdoctoral fellow and co-lead author on the research, which is scheduled to publish Dec. 1 in Science. Former graduate student Nicholas Steinmetz was the other co-lead author, who carried out the neurophysiology experiments in the lab of Tirin Moore, a professor of neurobiology and one of the senior authors.
Cycling on and off
Understanding these newly discovered cycles requires knowing a bit about how the brain is organized. If you were to poke a pin directly into the brain, all the brain cells you’d hit would respond to the same types of things. In one column they might all be responding to objects in a particular part of the visual field – the upper right, for example.
The team used what amounts to sets of very sensitive pins that can record activity from a column of neurons in the brain. In the past, people had known that individual neurons go through phases of being more or less active, but with this probe they saw for the first time that all the neurons in a given column cycled together between firing very rapidly then firing at a much slower rate, similar to coordinated cycles in sleep.
“During an on state the neurons all start firing rapidly,” said Kwabena Boahen, a professor of bioengineering and electrical engineering at Stanford and a senior author on the paper. “Then all of a sudden they just switch to a low firing rate. This on and off switching is happening all the time, as if the neurons are flipping a coin to decide if they are going to be on or off.”
Those cycles, which occur on the order of seconds or fractions of seconds, weren’t as visible when awake because the wave doesn’t propagate much beyond that column, unlike in sleep when the wave spreads across almost the entire brain and is easy to detect.
Pay attention
The team found that the higher and lower activity states relate to the ability to respond to the world. The group had their probe in a region of the brain in monkeys that specifically detects one part of the visual world. The monkeys had been trained to pay attention to a cue indicating that something in a particular part of the visual field – the upper right, say, or the lower left – was about to change slightly. The monkeys then got a treat if they correctly identified that they’d seen that change.
When the team gave a cue to where a change might occur, the neurons within the column that senses that part of the world all began spending more time in the active state. In essence, they all continued flipping between states in unison, but they spent more time in the active state if they were paying attention. If the stimulus change came when the cells were in a more active state, the monkey was also more likely to correctly identify the change.
“The monkey is very good at detecting stimulus changes when neurons in that column are in the on state but not in the off state,” Engel said. Even when the monkey knew to pay attention to a particular area, if the neurons cycled to a lower activity state the monkey frequently missed stimulus change.
Engel said this finding is something that might be familiar to many people. Sometimes you think you are paying attention, she pointed out, but you will still miss things.
The scientists said the findings also relate to previous work, which found that more alert animals and humans tend to have pupils that are more dilated. In the current work, when the brain cells were spending more time in an active state the monkey’s pupils were also more dilated. The findings demonstrate an interaction between synchronous oscillations in the brain, attention to a task and external signs of alertness.
“It seems that the mechanisms underlying attention and arousal are quite interdependent,” Moore said.
Low energy states
A question that comes out of this work is why the neurons cycle into a lower activity state when we’re awake. Why not just stay in the more active state all the time in case that’s when the saber tooth tiger attacks?
One answer could relate to energy. “There is a metabolic cost associated with neurons firing all the time,” Boahen said. The brain uses a lot of energy and maybe giving the cells a chance to do the energetic equivalent of sitting down allows the brain to save energy.
Also, when neurons are very active they generate cellular byproducts that can damage the cells. Engel pointed out that the low-activity states could allow time to clear out this neuronal waste.
“This paper suggests places to look for these answers,” Engel said.
ABOUT THIS SLEEP RESEARCH ARTICLE
Additional co-authors include colleagues from Newcastle University. Kwabena Boahen is also a member of Stanford Bio-X and the Stanford Neurosciences Institute. Tirin Moore is also an HHMI investigator as well as a member of Stanford Bio-X, the Stanford Neurosciences Institute and the Child Health Research Institute.
Funding: The work was funded by the NIH, Stanford NeuroVentures, the HHMI, the MRC and the Wellcome Trust.
Source: Amy Adams – Stanford Image Source: NeuroscienceNews.com image is credited to Wassermann/NINDS and is in the public domain.
Original Research:Abstract for “Selective modulation of cortical state during spatial attention” by Tatiana A. Engel, Nicholas A. Steinmetz, Marc A. Gieselmann, Alexander Thiele, Tirin Moore, and Kwabena Boahen in Science. Published online December 1 2016 doi:10.1126/science.aag1420
Abstract
Selective modulation of cortical state during spatial attention
Neocortical activity is permeated with endogenously generated fluctuations, but how these dynamics affect goal-directed behavior remains a mystery. We found that ensemble neural activity in primate visual cortex spontaneously fluctuated between phases of vigorous (On) and faint (Off) spiking synchronously across cortical layers. These On-Off dynamics, reflecting global changes in cortical state, were also modulated at a local scale during selective attention. Moreover, the momentary phase of local ensemble activity predicted behavioral performance. Our results show that cortical state is controlled locally within a cortical map according to cognitive demands and reveal the impact of these local changes in cortical state on goal-directed behavior.
“Selective modulation of cortical state during spatial attention” by Tatiana A. Engel, Nicholas A. Steinmetz, Marc A. Gieselmann, Alexander Thiele, Tirin Moore, and Kwabena Boahen in Science. Published online December 1 2016 doi:10.1126/science.aag1420
Summary: Researchers report on a link between bone mineral density and serotonergic synthesis in preclinical models of Alzheimer’s disease.
Source: NEOMED.
More than five million Americans are living with Alzheimer’s disease. Along with being the sixth leading cause of death in the U.S., NeuroscienceNews.com image is in the public domain.
Researchers at NEOMED have just identified a major connection between areas of the brainstem – the ancient area that controls mood, sleep and metabolism – and detrimental changes to bone in a preclinical model of Alzheimer’s disease (AD). The study, titled “Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease,” is led by Christine Dengler-Crish, Ph.D., assistant professor of pharmaceutical sciences, and anatomy and neurobiology, and will be published in the upcoming issue of the Journal of Alzheimer’s Disease, an international multidisciplinary journal that reports progress in understanding the causes, symptoms, and treatment of Alzheimer’s.
More than five million Americans are living with Alzheimer’s disease. Along with being the sixth leading cause of death in the U.S., Alzheimer’s has major social, emotional and financial consequences for patients and their families. Incurable and seemingly unstoppable, less than 5 percent of AD cases are due to a clear genetic reason, so it is hard to predict who will be at risk for acquiring this devastating disease.
Dr. Dengler-Crish and her research team that included graduate students Matthew Smith (NEOMED) and Gina Wilson (Kent State University) report that early reductions in bone mineral density (BMD) that occur in a preclinical model of AD are due to degeneration in an area of the brainstem that produces the majority of the brain’s serotonin — a neurochemical that controls mood and sleep, which are two processes that are also affected early in AD.
One’s bones may be one of the earliest indicators of brain degeneration in Alzheimer’s disease
Reduced BMD, which sometimes leads to osteoporosis, translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. Furthermore, Dr. Dengler-Crish’s research suggests that early bone loss and serotonin deficiency in AD may tell us something very important about how we approach diagnosing and treating this disease.
“Measurement of bone density, which is routinely performed in the clinic, could serve as a useful biomarker for assessing AD risk in our aging population,” notes Dr. Dengler-Crish. “The findings of this study motivate us to explore the serotonin system as a potential new therapeutic target for this devastating disease.”
Dengler-Crish, who received her bachelor’s degree from Baldwin Wallace University, her master’s in psychology from the University of Illinois at Chicago and her Ph.D. in neuroscience from Vanderbilt University, has now been named an associate editor for the Journal of Alzheimer’s Disease. She is excited to facilitate the work of other scientists in this important area. “I am thrilled to be able to assist the publication of researchers’ innovative work, here and across the world, that is desperately needed to combat these currently incurable chronic diseases. Now more than ever, there is hope that we soon will be able to slow, stop or reverse the progression of these destructive neurodegenerative conditions.”
“This is extremely exciting and has significant translational potential and relevance to early detection of the disease,” noted Jason R Richardson, Ph.D., DABT, director for Neurodegenerative Disease and Aging Research at NEOMED.
ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE
Source: Roderick Ingram – NEOMED Image Source: NeuroscienceNews.com image is in the public domain.
Original Research:Abstract for “Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease” by Dengler-Crish, Christine M.; Smith, Matthew A.; and Wilson, Gina N. in Journal of Alzheimer’s Disease. November 3 2016 doi:10.3233/JAD-160658
Abstract
Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease
Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate the rate in patients with Alzheimer’s disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome, changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2–6 months of age–time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)–a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in the tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.
“Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer’s Disease” by Dengler-Crish, Christine M.; Smith, Matthew A.; and Wilson, Gina N. in Journal of Alzheimer’s Disease. November 3 2016 doi:10.3233/JAD-160658
Summary: Aquaporin-4 could be a potential target for preventing and treating Alzheimer’s disease, a new study reports.
Source: OHSU.
Two images compare brain scans from an older individual who had Alzheimer’s (on the left) with an older cognitively healthy individual (n the right). The red fluorescence is the membrane protein aquaporin-4. The cognitively healthy individual has relatively even aquaporin-4 expression throughout the tissue and a stark enhancement of expression around the blood vessel, whereas the individual with Alzheimer’s has uneven, “patchy” expression of aquaporin-4. Neurosciencenews image is credited to OHSU.
OHSU researchers compare prevalence of aquaporin-4 in the brains of those who had Alzheimer’s to those who didn’t have the disease.
A new scientific discovery may provide a future avenue for treatment and prevention of Alzheimer’s disease.
A study published Nov. 28 in the journal JAMA Neurology examined aquaporin-4, a type of membrane protein in the brain. Using brains donated for scientific research, researchers at OHSU discovered a correlation between the prevalence of aquaporin-4 among older people who did not suffer from Alzheimer’s as compared to those who had the disease.
“It suggests that aquaporin-4 might be a useful target in preventing and treating Alzheimer’s disease,” said senior author Jeffrey Iliff, Ph.D., an Assistant Professor in the Department of Anesthesiology and Perioperative Medicine in the OHSU School of Medicine. “However, we aren’t under any illusion that if we could just fix this one thing, then we’d be able to cure Alzheimer’s Disease.”
Alzheimer’sis a progressive disease, most often associated with aging, that causes problems with memory, thinking and behavior. It is the leading cause of dementia worldwide and is currently the sixth leading cause of death in the United States. The disease has no known cure but there are treatments available for some of its symptoms.
Aquaporin-4 is a key part of a brain-wide network of channels, collectively known as the glymphatic system, that permits cerebral-spinal fluid from outside the brain to wash away proteins such as amyloid and tau that build up within the brain. These proteins tend to accumulate in the brains of some people suffering from Alzheimer’s, which may play a role in destroying nerve cells in the brain over time.
“This system, and the failure of the system, may be one of many things that goes wrong in people with Alzheimer’s disease,” Iliff said.
The study closely examined 79 brains donated through the Oregon Brain Bank, a part of the OHSU Layton Aging and Alzheimer’s Disease Center. They were separated into three groups: People younger than 60 without a history of neurological disease; people older than 60 with a history of Alzheimer’s; and people older than 60 without Alzheimer’s.
Researchers found that in the brains of younger people and older people without Alzheimer’s, the aquaporin-4 protein was well organized, lining the blood vessels of the brain. However within the brains of people with Alzheimer’s, the aquaporin-4 protein appeared disorganized, which may reflect an inability of these brains to efficiently clear away wastes like amyloid beta. The study concluded that future research focusing on aquaporin-4 – either through its form or function – may ultimately lead to medication to treat or prevent Alzheimer’s disease.
In 2015, a multidisciplinary team of scientists from OHSU led by Iliff was awarded a $1.4 million grant from the Paul G. Allen Family Foundation to use to develop new imaging techniques based on MRI to see these processes at work in the aging human brain for the first time.
ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE
In addition to Iliff, co-authors included Douglas M. Zeppenfeld; Matthew Simon, J. Douglas Haswell, and Daryl D’Abreo of the OHSU Department of Anesthesiology and Perioperative Medicine; Charles Murchison, Joseph F. Quinn, M.D., and Jeffrey Kaye, M.D., of the OHSU Department of Neurology; and Marjorie R. Grafe, M.D., Ph.D., and Randall L. Woltjer, M.D., Ph.D., of the Department of Pathology.
Funding: This work was supported by funding from the American Heart Association, grant 12SDG11820014, the Oregon Partnership for Alzheimer’s Research, grants from the Research and Development Office of the Department of Veterans Affairs and the National Institutes of Health (NS089709), including Alzheimer’s Disease Center grant AG08017 from the National Institute on Aging that supported the longitudinal follow-up and subsequent brain autopsies providing the human brain samples used in this study.
Image Source:This NeuroscienceNews.com image is credited to OHSU.
Original Research:Full open access research for “Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains” by Douglas M. Zeppenfeld, BS; Matthew Simon, BS1; J. Douglas Haswell, BS1; Daryl D’Abreo1; Charles Murchison, MS; Joseph F. Quinn, MD; Marjorie R. Grafe, MD, PhD; Randall L. Woltjer, MD, PhD; Jeffrey Kaye, MD; and Jeffrey J. Iliff, PhD in JAMA Neurology. Published online November 28 2016 doi:10.1001/jamaneurol.2016.4370
Abstract
Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains
Importance Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain.
Objectives To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology.
Design, Setting, and Participants Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact “young” individuals aged younger than 60 years (range, 33-57 years), cognitively intact “aged” individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD).
Main Outcomes and Measures Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated.
Results Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = −2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006).
Conclusions and Relevance In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.
“Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains” by Douglas M. Zeppenfeld, BS; Matthew Simon, BS1; J. Douglas Haswell, BS1; Daryl D’Abreo1; Charles Murchison, MS; Joseph F. Quinn, MD; Marjorie R. Grafe, MD, PhD; Randall L. Woltjer, MD, PhD; Jeffrey Kaye, MD; and Jeffrey J. Iliff, PhD in JAMA Neurology. Published online November 28 2016 doi:10.1001/jamaneurol.2016.4370
The finding by USC researchers may explain how Alzheimer’s and Parkinson’s affect men and women
The fruit fly genome sequence, which shares similarities with the human genome, is useful in many research labs. (Photo/Christopher S. Newhard, Rensselaer Polytechnic Institute)
The differences in how male and female fruit flies resist and adapt to oxidative stress may shed new light on how age-related diseases such as Alzheimer’s and Parkinson’s affect men and women differently.
Through a series of tests, USC researchers found that female fruit flies were better able to respond to stress caused by a common oxidant, hydrogen peroxide (produced naturally in the body for cell signaling and to combat infection), than males. However, males were better able to adapt to another oxidant, paraquat, a common herbicide.
Both oxidants have been implicated in human diseases. Elevated levels of hydrogen peroxide are found in patients suffering from a stroke, a heart attack or Alzheimer’s disease. Paraquat is one of the environmental toxins that can damage the neurons involved in Parkinson’s disease, which attacks the nervous system.
The male and female responses to the stress seem to differ in part because of a protein, Lon protease, that localizes to mitochondria, the researchers found.
Basic similarities
Fruit flies share many fundamental similarities with humans, including the gene for this protective protein, which helps cells respond to oxidative stress, said corresponding author John Tower, professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences and the USC Leonard Davis School of Gerontology.
Oxidative stress occurs when unstable, uncharged molecules — free radicals — overwhelm the body’s antioxidants, then react with other substances to damage cells or generate abnormal ones. The damage from this stress accumulates with age.
“The Lon protease breaks down proteins that are damaged by oxidative stress and it protects cells from the damaged proteins’ ill effects,” Tower said.
The researchers’ findings, published in the journal Current Biology on Dec. 1, indicate the need for further investigation into sex-based differences in the biological responses of men and women, particularly as scientists consider new ways to treat age-related diseases, Tower said.
“Many of the illnesses related to oxidative stress have different prevalence rates between men and women,” he said. “For instance, Alzheimer’s disease and diabetes-related heart disease affects more women than men, while Parkinson’s disease and cancer affect more men than women.”
In both flies and humans, Lon protease is found in the mitochondria, the capsule-like organelles deemed the powerhouse of cells that convert nutrients into energy. Mitochondria contain their own DNA and are inherited from the mother. Increasingly, they are the focus of age-related research as scientists have uncovered links between mitochondrial function and cardiovascular disease, diabetes, Alzheimer’s and Parkinson’s and other diseases, Tower said.
“Many human diseases involve chronic oxidative stress, and mitochondria are the main source,” Tower said.
Stress test
To test the flies’ resistance to oxidative stress, researchers first exposed them to small amounts of one of two common oxidants — hydrogen peroxide or paraquat.
If the flies developed resistance to the oxidant by producing more Lon protease, they could survive larger, semi-lethal doses of the chemical. The team found that only the female flies could adapt to hydrogen peroxide exposure, while only the male flies could resist the heavier paraquat dose.
To confirm the role of sex in the different responses, researchers genetically manipulated male flies to develop into “pseudo-females” with female body characteristics. These pseudo-female flies adapted to hydrogen peroxide but not paraquat, indicating the same resistance as the natural female flies.
Illustrating a possible reason for the sex discrepancy, the researchers characterized key differences in the Lon protease between the sexes. Female flies expressed an extra version, or isoform, of the protein that varied in size compared to the isoforms shared between the sexes. Sex-specific expression of Lon protein isoforms was also observed mouse tissues.
“These different-size Lon isoforms may help regulate sex-specific stress resistance,” Tower said.
The authors offered a few hypotheses as reasons for the differences in male and female responses to hydrogen peroxide. For instance, because mitochondria are inherited from the mother, it’s possible that natural selection only optimizes the function and interactions of mitochondrial genes in females, they wrote. Females may have evolved to better respond to hydrogen peroxide because it is a normal signaling molecule produced by mitochondria.
The researchers also offered possible explanations for the males’ adaptation and resistance to paraquat. Males express greater dopamine receptor levels, which may have helped them adapt to oxidative stress from paraquat. While that response may help them adapt to low stress, however, it may make them a more vulnerable target to toxic stress, such as Parkinson’s disease.
Other study authors were Laura C. D. Pomatto, Caroline Carney, Brenda Shen, Sarah Wong, Kelly Halaszynski, and Kelvin J. A. Davies, all of USC Davis, as well as Matthew P. Salomon of USC Dornsife and the John Wayne Cancer Institute at Providence Saint John’s Health Center.
The research was funded by the National Science Foundation (grant DGE-1418060) and the National Institutes of Health/National Institute of Environmental Health Sciences (grant ES03598), the NIH/National Institute on Aging (grant AG011833) and pilot funding from the Southern California Environmental Health Sciences Center (grant 5P30ES007048).
Gut microbes may play a critical role in the development of Parkinson's, according to groundbreaking new research published on Thursday 1 December in Cell.
We hope this will trigger more research that will ultimately revolutionise treatment options for Parkinson's
Dr Arthur Roach, Director of Research
The US team showed that treatment with antibiotics was able to reduce movement symptoms and the build-up of clumps of alpha-synuclein in mice with a gene that causes the condition.
The findings could lead to new treatments that can slow, stop or even prevent the development of the condition.
What the team did
Researchers based at the California Institute of Technology studied mice with a small genetic change that causes them to produce too much of the protein alpha-synuclein.
As the mice age, they naturally develop clumps of alpha-synuclein inside brain areas involved in controlling movement, and mobility problems similar to those experienced by people with Parkinson's.
The researchers raised the mice in either normal conditions or in a germ-free environment. Remarkably, mice raised in the germ-free cages had almost normal mobility and much reduced build-up of protein clumps in their brains.
Treating mice raised in normal conditions with antibiotics had a similar protective effect.
Crucially, when mice raised in the germ-free cages were treated with chemicals released by gut microbes or gut microbes from people with Parkinson's their movement problems worsened.
Developing new treatments
Dr Arthur Roach, Director of Research at Parkinson's UK, says:
"In recent years, evidence has been growing that Parkinson's may begin in the gut, but the chain of events involved has so far remained a mystery.
This study provides a fresh insight into how Parkinson's develops
"This paper shows for the first time a way in which one of the key players in Parkinson's, the protein alpha-synuclein, may have its actions in the brain modified by gut bacteria.
"The greatest need in Parkinson's research is to develop treatments that can stop or slow down the processes that first lead to the condition, something no current treatments can do.
"This work opens an exciting new avenue of study on the gut-brain connection in Parkinson's. There are still many questions to answer but we hope this will trigger more research that will ultimately revolutionise treatment options for Parkinson's."
What are the next steps?
This study provides a fresh insight into how Parkinson's develops and exciting new opportunities to develop treatments that can intervene.
Current antibiotics are not a viable option as we know that long-term, high-strength antibiotic use comes with significant health risks.
Up to a trillion microbes live in our gut. Many are beneficial so the next step is to pinpoint those that are harmful so that treatments can be developed to target the damaging ones while leaving the beneficial ones unharmed.
It takes many years to turn a scientific discovery like this one into a new treatment that can be tested in people. That's why we are investing in taking the best research ideas forwards faster through our virtual biotech.
