Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson’s. But the new study suggests that a dysfunction in the neuron’s synapses — the tiny gap across which a neuron can send an impulse to another neuron — leads to deficits in dopamine and precedes the neurodegeneration.

Parkinson’s disease affects 1% to 2% of the population and is characterized by resting tremor, rigidity and bradykinesia (slowness of movement). These motor symptoms are due to the progressive loss of dopaminergic neurons in the midbrain.

The findings, which will be published Sept. 15 in Neuron, open a new avenue for therapies, the scientists said.

“We showed that dopaminergic synapses become dysfunctional before neuronal death occurs,” said lead author Dr. Dimitri Krainc, chair of neurology at Northwestern University Feinberg School of Medicine and director of the Simpson Querrey Center for Neurogenetics. “Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy.”

The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans, as highlighted in Krainc’s research recently published in Science.

Northwestern scientists found that dopaminergic synapses are not functioning correctly in various genetic forms of Parkinson’s disease. This work, together with other recent studies by Krainc’s lab, addresses one of the major gaps in the field: how different genes linked to Parkinson’s lead to degeneration of human dopaminergic neurons.

Neuronal recycling plant

Imagine two workers in a neuronal recycling plant. It’s their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of.

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson’s disease because of ineffective mitophagy.

The story of two sisters whose disease helped advance Parkinson’s research

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson’s disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48.

The reason for the disparity led to an important new discovery by Krainc and his group. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson’s.

“There must be a complete loss of Parkin to cause Parkinson’s disease. So, why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?” Krainc asked.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal — unrelated to its recycling work — where it controls dopamine release. With this new understanding of what went wrong for the sister, Northwestern scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons.

“We discovered a new mechanism to activate Parkin in patient neurons,” Krainc said. “Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson’s.”

The first author of the study is Pingping Song, research assistant professor in Krainc’s lab. Other authors are Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern and Kalle Gehring from McGill University.

The title of the article is “Parkinson’s disease linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.”

This work was supported by National Institutes of Health grants R01NS076054, R3710 NS096241, R35 NS122257 and NS121174, all from the National Institute of Neurological Disorders and Stroke.

Jeyhan Kartaltepe, associate professor in the School of Physics and Astronomy, and Rebecca Larson, postdoctoral research associate, co-authored a paper, “Confirmation and refutation of very luminous galaxies in the early Universe,” published in Nature confirming very bright galaxies in the early universe, while also disproving the identification of what would have been the most distant galaxy ever found.

Kartaltepe and Larson, along with co-authors from around the world, studied the redshift (or displacement of the spectrum of an object toward longer, red wavelengths) of several specific galaxies to see how much the light shifted, which indicates how far away the galaxies are. The CEERS team focused on Maisie’s Galaxy, which was theorized to have a redshift of z ≈ 11.5, while a team in Scotland researched a nearby galaxy that they believed could have a redshift of z ≈ 16, far larger than any ever found before.

To examine further, the two teams partnered on a proposal to receive follow-up spectroscopy. When the new data came in, the teams were able to precisely measure the redshifts of both of these candidates, along with a few others.

“Spectra are how you really confirm what a galaxy’s redshift is,” explained Kartaltepe. “For these two galaxies, the answer was very clear — the spectra look completely different. We confirmed that Maisie’s Galaxy is at the high redshift we thought it was.”

The group also found that because of a coincidence that mimicked the colors of a high redshift galaxy, the other galaxy is not at a redshift of z ≈ 16, but at a redshift of z ≈ 4.9. Both the initial and follow-up data from JWST turned the theories into discoveries.

“Not only did JWST find these galaxies we didn’t know about before, but then it confirmed the redshift for them,” said Larson. “This paper in particular speaks to the power of not only JWST finding galaxies in the really early universe but also confirming and characterizing them.”

The research and the paper would not have been possible without dedicated collaboration between the CEERS team and the team in Scotland. Instead of working separately on their individual galaxies and submitting separate proposals, the partnership allowed for the follow-up spectroscopy to be accepted, and the subsequent analysis to be conducted efficiently, leading to new information about the universe.

When researching the data from JWST, scientists aim to find the highest redshift galaxies, or the most distant galaxies. Finding galaxies in the very early universe was one of the goals for the JWST. These and other early discoveries have proven the success of the telescope, even this early in its existence.

“It shows us how powerful the telescope is and its ability to do the things it was built to do,” said Kartaltepe. “In some ways, it performs even better than we expected. We are already learning so much about the universe early on in JWST’s mission. I think going forward we’re going to be able to build large samples over larger areas and really be able to dig deeper into the physical characteristics of galaxies in the early universe.”

The pregnancy complication affects up to eight per cent of pregnancies globally and is the leading cause of maternal and fetal mortality due to premature delivery, complications with the placenta and lack of oxygen.

The research, led by Drs. Kun Ping Lu and Xiao Zhen Zhou at Western, and Drs. Surendra Sharma and Sukanta Jash at Brown, has identified a toxic protein, cis P-tau, in the blood and placenta of preeclampsia patients.

According to the study published in Nature Communications, cis P-tau is a central circulating driver of preeclampsia — a “troublemaker” that plays a major role in causing the deadly complication.

“The root cause of preeclampsia has (so far) remained unknown, and without a known cause there has been no cure. Preterm delivery is the only life-saving measure,” said Lu, professor of biochemistry and oncology at Schulich School of Medicine & Dentistry. Lu is also a Western Research Chair in Biotherapeutics.

“Our study identifies cis P-tau as a crucial culprit and biomarker for preeclampsia. It can be used for early diagnosis of the complication and is a crucial therapeutic target,” said Sharma, who recently retired from his Brown roles as a professor of pathology and laboratory medicine (research) and professor of pediatrics (research).

In 2016, Sharma, a leading preeclampsia researcher, and his team had identified that preeclampsia and diseases like Alzheimer’s had similar root causes related to protein issues. This research builds on that finding.

Until now, cis P-tau was mainly associated with neurological disorders like Alzheimer’s disease, traumatic brain injuries (TBI) and stroke. This association was discovered by Lu and Zhou in 2015 as a result of their decades of research on the role of tau protein in cancer and Alzheimer’s.

An antibody developed by Zhou in 2012 to target only the toxic protein while leaving its healthy counterpart unscathed is currently undergoing clinical trials in human patients suffering from TBI and Alzheimer’s Disease. The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions.

The researchers were curious whether the same antibody could work as a potential treatment for preeclampsia. Upon testing the antibody in mouse models they found astonishing results.

“In this study, we found the cis P-tau antibody efficiently depleted the toxic protein in the blood and placenta, and corrected all features associated with preeclampsia in mice. Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine and fetal growth restriction, among others, were eliminated and pregnancy was normal,” said Sharma.

Sharma and his team at Brown have been working on developing an assay for early detection of preeclampsia and therapies to treat the condition. He believes the findings of this study have brought them closer to their goal.

Black and Hispanic women more susceptible

The tragic death of American track and field champion Tori Bowie earlier this year put the spotlight on preeclampsia, which disproportionately impacts Black and Hispanic women.

A gold, silver and bronze medalist in the 2016 Olympic Games, Bowie, 32, was found dead in her bed on May 2, 2023, while approximately eight months pregnant. According to the autopsy report the complications may have involved eclampsia — a severe form of preeclampsia.

“Research has shown that women of certain races have genes that could possibly lead to higher than average blood pressure levels, eventually creating conditions for preeclampsia during pregnancy. However, it’s also true that in many low socio-economic countries there’s no registry to record PE cases. So, its link to other environmental factors is still unclear,” said Sharma.

Preeclampsia and the brain

Recent research has also thrown light on preeclampsia’s long-term impacts and possible links to brain health.

“Preeclampsia presents immediate dangers to both the mother and fetus, but its long-term effects are less understood and still unfolding,” said Sharma. “Research has suggested a heightened risk of dementia later in life for both mothers who have experienced preeclampsia and their children.” However, the causal link between preeclampsia and dementia is not known.

The researchers say this new study has pinpointed a potential underlying cause of the complex relationship between preeclampsia and brain health.

“Our study adds another layer to this complexity. For the first time, we’ve identified significant levels of cis P-tau outside the brain in the placenta and blood of preeclampsia patients. This suggests a deeper connection between preeclampsia and brain-related issues,” said Jash, the lead author of the study.

As researchers delve deeper, how our bodies respond to stress is also emerging as a potential factor in the onset of preeclampsia.

“Although genetics play a role, factors like stress could be an important piece of the puzzle. Understanding how stress and other environmental factors intersect with biological markers like cis P-tau may offer a more complete picture,” said Jash, assistant professor of molecular biology, cell biology and biochemistry (research) and pediatrics (research) at Brown.

A stress-response enzyme called Pin1

In 1996 and 1997, Lu and Zhou made the groundbreaking discovery of Pin1, which turns out to be a stress-response enzyme. This is a specific protein in the cells that becomes active or changes its behaviour in response to stressors, such as environmental challenges, toxins or physiological changes.

“Pin1 plays a pivotal role in keeping proteins, including the tau protein, in the functional shape during stress. When Pin1 becomes inactivated, it leads to the formation of a toxic, misshapen, variant of tau — cis P-tau,” said Zhou, associate professor, pathology and laboratory medicine at Schulich Medicine & Dentistry.

Interestingly, Pin1 is a key player in cancer signalling networks, turning on numerous cancer-causing proteins and turning off many cancer-suppressing ones. Found in high levels in most human cancers, it’s particularly active in cancer stem cells, which are thought to be central to starting and spreading tumors and are hard to target with existing treatments.

“Essentially, when Pin1 is activated, it can lead to cancer. On the other hand, when there’s a decrease or deactivation in Pin1, it results in the formation of the toxic protein cis P-tau, which leads to memory loss in Alzheimer’s and after TBI or stroke. Now, we’ve uncovered its connection to preeclampsia as well,” said Zhou.

“The results have far-reaching implications. This could revolutionize how we understand and treat a range of conditions, from pregnancy-related issues to brain disorders,” said Lu.

Lu and Sharma had met at Brown in 2019, where Lu was invited to give a lecture on his research. Following an engaging session and a few dinners together, a collaboration between the Western researchers and Brown was forged.

“Science surprises us. I had never thought of working on finding a therapy for preeclampsia. It also shows that a collaboration can be transformative.”

Led by Saptarshi Das, associate professor of engineering science and mechanics at Penn State, the team published their work on September 15 in Nature Communication.

“Robots make decisions based on the environment they are in, but their sensors do not generally talk to each other,” said Das, who also has joint appointments in electrical engineering and in materials science and engineering. “A collective decision can be made through a sensor processing unit, but is that the most efficient or effective method? In the human brain, one sense can influence another and allow the person to better judge a situation.”

For instance, a car might have one sensor scanning for obstacles, while another senses darkness to modulate the intensity of the headlights. Individually, these sensors relay information to a central unit which then instructs the car to brake or adjust the headlights. According to Das, this process consumes more energy. Allowing sensors to communicate directly with each other can be more efficient in terms of energy and speed — particularly when the inputs from both are faint.

“Biology enables small organisms to thrive in environments with limited resources, minimizing energy consumption in the process,” said Das, who is also affiliated with the Materials Research Institute. “The requirements for different sensors are based on the context — in a dark forest, you’d rely more on listening than seeing, but we don’t make decisions based on just one sense. We have a complete sense of our surroundings, and our decision making is based on the integration of what we’re seeing, hearing, touching, smelling, etcetera. The senses evolved together in biology, but separately in AI. In this work, we’re looking to combine sensors and mimic how our brains actually work.”

The team focused on integrating a tactile sensor and a visual sensor so that the output of one sensor modifies the other, with the help of visual memory. According to Muhtasim Ul Karim Sadaf, a third-year doctoral student in engineering science and mechanics, even a short-lived flash of light can significantly enhance the chance of successful movement through a dark room.

“This is because visual memory can subsequently influence and aid the tactile responses for navigation,” Sadaf said. “This would not be possible if our visual and tactile cortex were to respond to their respective unimodal cues alone. We have a photo memory effect, where light shines and we can remember. We incorporated that ability into a device through a transistor that provides the same response.”

The researchers fabricated the multisensory neuron by connecting a tactile sensor to a phototransistor based on a monolayer of molybdenum disulfide, a compound that exhibits unique electrical and optical characteristics useful for detecting light and supporting transistors. The sensor generates electrical spikes in a manner reminiscent of neurons processing information, allowing it to integrate both visual and tactile cues.

It’s the equivalent of seeing an “on” light on the stove and feeling heat coming off of a burner — seeing the light on doesn’t necessarily mean the burner is hot yet, but a hand only needs to feel a nanosecond of heat before the body reacts and pulls the hand away from the potential danger. The input of light and heat triggered signals that induced the hand’s response. In this case, the researchers measured the artificial neuron’s version of this by seeing signaling outputs resulted from visual and tactile input cues.

To simulate touch input, the tactile sensor used triboelectric effect, in which two layers slide against one another to produce electricity, meaning the touch stimuli was encoded into electrical impulses. To simulate visual input, the researchers shined a light into the monolayer molybdenum disulfide photo memtransistor — or a transistor that can remember visual input, like how a person can hold onto the general layout of a room after a quick flash illuminates it.

They found that the sensory response of the neuron — simulated as electrical output — increased when both visual and tactile signals were weak.

“Interestingly, this effect resonates remarkably well with its biological counterpart — a visual memory naturally enhances the sensitivity to tactile stimulus,” said co-first author Najam U Sakib, a third-year doctoral student in engineering science and mechanics. “When cues are weak, you need to combine them to better understand the information, and that’s what we saw in the results.”

Das explained that an artificial multisensory neuron system could enhance sensor technology’s efficiency, paving the way for more eco-friendly AI uses. As a result, robots, drones and self-driving vehicles could navigate their environment more effectively while using less energy.

“The super additive summation of weak visual and tactile cues is the key accomplishment of our research,” said co-author Andrew Pannone, a fourth-year doctoral student in engineering science and mechanics. “For this work, we only looked into two senses. We’re working to identify the proper scenario to incorporate more senses and see what benefits they may offer.”

Harikrishnan Ravichandran, a fourth-year doctoral student in engineering science and mechanics at Penn State, also co-authored this paper.

The Army Research Office and the National Science Foundation supported this work.

Now, UNC School of Medicine scientists and colleagues are figuring out which of these variants have a causal effect in the development of the schizophrenia. They are finding that some of genetic variants regulate or alter the expression of genes involved in the condition.

Published in the journal Cell Genomics, this research marks a big step forward in our understanding of the genetic basis of schizophrenia.

“Our findings not only provide insights into the intricate regulatory landscape of genes, but also propose a groundbreaking approach to decoding the cumulative effect of genetic variants on gene regulation in individuals with schizophrenia,” said senior author Hyejung Won, Ph.D., associate professor of genetics at the UNC School of Medicine. “This comprehension could potentially pave a path for more precise interventions and therapies in the future. Right now, therapeutic options are limited, and some people do not respond to drugs available.”

For this study, Won and first authors Jessica McAfee and Sool Lee, both UNC-Chapel Hill graduate students, led a team of researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy to explore the genetic variants already linked to the risk of schizophrenia through GWAS research. Their goal was to figure out a way to tease apart meaningless variants from those with potential for biological activity important for developing schizophrenia. This isn’t easy for a few reasons, one of which is that genetic variants are often inherited together from parents. So, right next to each other could be two genetic variants associated with the condition — one might be important for gene expression that plays a major role in the condition, but the other variant might not have any role in the condition.

To tackle this problem, the researchers used a special technique called a massively parallel reporter assay (MPRA) — essentially a genetic sequencing technique that can parse which variants trigger gene expression and which ones don’t. To use this method, the researchers introduced the 5,000 variants into human brain cells in a dish, cells that are essential for early brain development. These variants may or may not cause the expression of their downstream gene and genetic barcode. The barcode, a 20bp DNA sequence, is unique to each variant. This is what the group uses to distinguish the variant sequences. The MPRA revealed 439 genetic variations with actual biological effects, meaning they can alter expression of gene.

“Traditionally, scientists have used other epigenetic data, such as transcription factor binding and biochemically defined enhancers, to identify variants with biological effects,” Won said. “However, these conventional methods failed to predict a large portion of variants we identified to have biological effects. Our work points to a wealth of unexplored variants with biological effects.”

To understand how these variants work together to influence gene activity, Won and colleagues developed a new model that combines data from MPRA with chromatin architecture of brain cells — that is, the genetic information important for how brain cell DNA is organized. By doing this, the researchers could connect these 439 variants to how genes are turned on or off.

“Schizophrenia is a complex condition that is highly heritable,” Won said. “To find these 439 potentially causal variants is a big step, but we still have a lot of work ahead to figure out the complicated genetic architecture that leads an individual to develop this condition. With that information in hand, we could begin to understand the biological mechanism underlying this complex disorder, which may eventually lead to targeted therapies.”

The authors of new research led by the University of Exeter have warned that women who discover, outside of a clinical setting, that they carry a disease-causing variant in one of the BRCA genes (BRCA1 or BRCA2) may be told their risk of breast cancer is 60-80 per cent. In fact, the risk could be less than 20 per cent if they do not have a close relative with the condition.

The warning has emerged in a paper published today in the Lancet journal eClinical Medicine. Until recently, women who received BRCA results did so because they attended clinic due to symptoms, or a family history of disease. The likelihood of certain BRCA variants causing breast cancer has been calculated based on this already high-risk group. However, many people now pay for home DNA testing kits, or are given results as part of taking part in genetic research, without ever having any personal link with breast cancer. The new research, funded by the Medical Research Council, was conducted to get a better idea of the true risk level of these BRCA variants in the general population.

The authors analysed more than 454,000 participants recruited between the ages of 40 and 69 in the UK Biobank study, which collects DNA samples and asks participants to report illness in themselves as well as parents and siblings. They found that simply carrying a disease-causing BRCA variant was linked to a breast cancer risk of 18 per cent (for BRCA2) and 23 per cent (for BRCA1) by age 60. Having a close relative who has had the condition elevated the risk to 24 per cent (for BRCA2) and 45 per cent (for BRCA1) .

Lead author Dr Leigh Jackson, of the University of Exeter Medical School, said more women were choosing to have breast cancer surgery, particularly since actress Angelina Jolie shared her family history of the disease and subsequent genetic test and surgery. But he said: “Being told you are at high genetic risk of disease can really influence levels of fear of a particular condition and the resulting action you may take. Up to 80 per cent risk of developing breast cancer is very different from 20 per cent. That difference could well influence the decision you make around whether you have invasive breast surgery. Some women may decide to go ahead with that procedure knowing that the risk is 20 per cent, but we want them to make an informed decision. We’d urge that anyone communicating cancer risk does so based on a detailed family history, not just genetics alone.”

The research team found a similar result when looking at genetic risk of Lynch syndrome, a genetic condition which increases the risk of colon cancer and some other cancers. The authors also concluded that genetic screening for these conditions in the general population could result in large numbers of people being exposed to needless scans or further procedures.

Co-author Professor Caroline Wright, of the University of Exeter Medical School, said: “Our findings will not just apply to breast and colorectal cancer. All risk estimates of genetic disease have so far largely been based on relatively high-risk groups who attend specialist clinics, so they will not necessarily translate to the general population. This finding has important ramifications for population screening using genome sequencing. We need to ensure we are carrying out research to find the true risk level, and also to be responsible in how we communicate risk, to avoid unnecessary fear and distress which may lead to avoidable procedures.”

If you’re given a high genetic risk of any disease outside of a clinical setting, we’d advise you to speak to your doctor, who will be able to take into account a range of factors including family history to assess whether the risk may be worth investigating further.

Professor Joerg Henning and his colleagues at The University of Queensland School of Veterinary Science have analysed data from the UQ-developed KoalaBASE.

“Car strikes, dog attacks and chlamydia-induced illnesses are injuring and killing an incredible number of koalas across the South East Queensland,” Professor Henning said.

“In the five years between 2009 and 2014, 52 per cent of reported wild koala deaths were caused by car strike, 34 per cent were from a chlamydia-related disease and 14 per cent were because of a dog attack.

“This equates to 1,431 koala deaths from a car strike, 943 chlamydia-related deaths, and 395 dog attack deaths in just five years.

“Remember that these deaths were just the reported cases, so the real numbers would be significantly higher.”

KoalaBASE has been collecting data since 1997 across 15 local government areas from the Fraser Coast, to the Scenic Rim and Darling Downs and the South Burnett.

Dr Ravi Dissanayake conducted the initial analysis, supervised by UQ colleagues and Professor Mark Stevenson at the University of Melbourne.

Data considered in the analysis included dog registration numbers, the human population and dwelling information, as well as road type and road length.

“This analysis is a useful starting point for more pro-active approaches to managing preventable wild koala mortality risk,” Professor Stevenson said.

“There are plenty of policies that could reduce car and dog impacts on South East Queensland’s dwindling wild koala populations.”

Professor Henning suggests that more road signs could alert motorists to reduce their speed in known koala habitat and activity areas.

“Construction of over and underpasses is also essential to ensure the safe movement of koalas through their habitat,” Professor Henning said.

“And information campaigns could help reduce the numbers of dog attacks on koalas by reminding owners to leash their dogs or keep them fenced in areas — it’s vitally important to reduce koala deaths caused by dogs.

“Our research included plenty of mapping, so we’re now keen to work with policymakers to identify specific areas where intervention efforts can help to reduce koala deaths.”