Tag Archives: #neurodegeneration

Researchers Identified An Immune Protein Tied To The Niemann-Pick Disease Type C (Neuroscience)

Niemann-Pick disease type C, long thought to be tied to cholesterol metabolism, may eventually be treated with immune inhibitors

UT Southwestern researchers have identified an immune protein tied to the rare neurodegenerative condition known as Niemann-Pick disease type C. The finding, made in mouse models and published online in Nature, could offer a powerful new therapeutic target for Niemann-Pick disease type C, a condition that was identified more than a century ago but still lacks effective treatments.

Nan Yan, Ph.D. © UTSMC

“Niemann-Pick disease has never been considered an immune disorder,” says study leader Nan Yan, Ph.D., associate professor of immunology and microbiology. “These findings put it in a whole new light.”

Niemann-Pick disease type C, which affects about 1 in every 150,000 people worldwide, has long been considered a disease of cholesterol metabolism and distribution, a topic well-studied at UT Southwestern, where faculty members Michael Brown, M.D., and Joseph Goldstein, M.D., won the Nobel Prize in 1985 for their discovery of low-density lipoprotein (LDL) receptors, which led to the development of statin drugs.

When the Npc1 gene is mutated, cholesterol isn’t sent where it’s needed in cells, causing the progressive decline in motor and intellectual abilities that characterize Niemann-Pick. Yan’s lab, which doesn’t study cholesterol metabolism, made its discovery by chance while researching an immune protein known as STING, short for stimulator of interferon genes.

STING is a critical part of the body’s defense against viruses, typically relying on another protein known as cyclic GMP-AMP synthase (cGAS) to sense DNA and turn on immune genes to fight off viral invaders. The cGAS enzyme was identified at UT Southwestern.  

STING journeys to different organelles to perform various tasks before it ends up in lysosomes, which serve as cellular garbage dumps. Disposal of STING is critical for an appropriate immune response, explains Yan; research from his lab and others has shown that when STING isn’t properly discarded, it continues to signal immune cells, leading to a variety of autoimmune conditions.

To determine what proteins interact with STING as it travels through cells, Yan and his colleagues used a technique called proximity labeling, which causes other proteins around a protein of interest to glow. After analyzing their data, Yan’s team was surprised to find that STING interacts with a protein that’s located on the surface of lysosomes and is produced by the Npc1 gene.

Because STING had never been implicated in Niemann-Pick disease type C, Yan and his team investigated whether it might play a role. The researchers removed the gene for STING from mice in which the Npc1 gene had also been deleted. Deleting Npc1 typically causes progressive problems in motor function, but animals with both the Npc1 and Sting genes deleted remained healthy.

Further research suggested that the protein produced by Npc1 has a binding site for STING that allows it to enter lysosomes for disposal. When the protein produced by Npc1 is missing, STING remains in cells, propagating Niemann-Pick disease type C. When Yan and his colleagues analyzed cells from human Niemann-Pick disease type C patients, they found that several immune-stimulating genes were overactive, as would be expected if STING disposal was defective.

In addition, Yan found that STING signaling is activated independently of cGAS in Niemann-Pick disease. This expands STING biology beyond its conventional role in host defense against infection.

Yan says that his lab and others are investigating the use of experimental drugs that inhibit STING to treat various autoimmune conditions. These compounds may also be useful for Niemann-Pick disease type C.

“If we can demonstrate that these compounds are effective in our animal models,” Yan says, “we may be able to offer an effective therapy to Niemann-Pick disease patients.”

Other UTSW researchers who contributed to this study include Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, and a variety of other UT Southwestern experts in neuroscience and cholesterol biology. This study also relied on technical support from UTSW’s Whole Brain MicroscopyProteomics CoreLive Cell Imaging Core and Transgenic Core facilities.

This work is supported by National Institutes of Health, Cancer Prevention and Research Institute of Texas, the Burroughs Wellcome Fund, and the Ara Parseghian Medical Research Foundation.

Brown, a Regental Professor, holds the W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Thomas Chair in Medicine. Goldstein, a Regental Professor, holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine. Yan is the Rita C. and William P. Clements, Jr. Scholar in Medical Research.

Featured image: Immunofluorescent staining of Npc1-deficient mouse cerebellum, with Purkinje neurons in red, activated microglia in green and nucleus in blue. Massive microglia infiltration and loss of Purkinje neurons cause severe neurological disease in Niemann-Pick disease type C. Credit: Ting-Ting Chu

Reference: Chu, TT., Tu, X., Yang, K. et al. Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C. Nature (2021). https://doi.org/10.1038/s41586-021-03762-2

Provided by UTSMC

Spinal Fluid Biomarkers Detect Neurodegeneration, Alzheimer’s Disease in Living Patients (Neuroscience)

Alzheimer’s Disease and other forms of neurodegeneration can be identified using a combination of biomarkers in cerebrospinal fluid of living patients, Penn researchers find

Alzheimer’s disease and related diseases can still only be confirmed in deceased patients’ brains via autopsy. Even so, the development of biomarkers can give patients and their families answers during life: Alzheimer’s disease can be accurately detected via peptides and proteins in a patient’s cerebrospinal fluids (CSF), which can be collected through a lumbar puncture and tested while the patient is alive. In 2018, a new framework suggested combining three Alzheimer’s disease biomarkers in CSF – pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N), collectively called ATN. According to recent research from the Perelman School of Medicine at the University of Pennsylvania, the ATN framework can be extended to detect another neurodegenerative condition: frontotemporal degeneration.

Patients with frontotemporal degeneration can experience a range of symptoms, including behavioral changes, executive dysfunction, and language impairments. Distinguishing frontotemporal degeneration from Alzheimer’s disease can be a challenge for clinicians: the symptoms of frontotemporal degeneration can sometimes overlap with Alzheimer’s disease, and a subset of patients can even have both pathologies. Biomarkers can fill the gap by providing evidence of whether Alzheimer’s pathology underlies a patient’s symptoms.

“CSF biomarkers work similarly to a pregnancy test, offering a simple positive or negative result when enough of a substance is detected. But like a pregnancy test, biomarkers for Alzheimer’s disease can provide false negatives or positives,” said lead investigator Katheryn A.Q. Cousins, PhD, a research associate in the Frontotemporal Degeneration Center in the Department of Neurology at Penn Medicine. “Alzheimer’s is a diverse disease, and it is common for other conditions to also be present in the brain. The ATN framework may provide a more complete look at a person’s diagnosis and give us a much richer understanding of not only Alzheimer’s disease, but other co-occurring neurodegenerative conditions. However, to accomplish this, additional biomarkers that can detect other neurodegenerative conditions are critically needed.”

The findings, published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, show that ATN incorporating neurofilament light chain (NfL) may provide a more accurate and precise diagnosis for patients with frontotemporal degeneration. NfL is a protein abundant in the brain, whose levels increase as degeneration progresses. Cousins’ work shows that CSF NfL may be a more accurate marker of neurodegeneration for patients with frontotemporal degeneration, including for Alzheimer’s disease.

“While the ATN framework is very exciting and offers much opportunity for patients with Alzheimer’s disease, these biomarkers don’t capture every case of the disease. We want to be able to detect and treat every patient with neurodegenerative disease as early as possible, and more research is needed to fully understand how biofluids track with the disease process,” said Cousins. “I am eager to conduct additional research into which patients might be missed by these markers, what they have in common, and what causes the pathological and clinical differences in the disease.”

This study was funded by the Swedish Research Council (2018-02532); the European Research Council, (681712); Swedish State Support for Clinical Research (ALFGBG-720931); the Alzheimer Drug Discovery Foundation (201809-2016862); the Swedish Alzheimer Foundation, (AF-742881); European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); and the Alzheimer’s Association Research Fellowship (AARF-16-44368).

Provided by Penn Medicine

Can Microbes Combat Neurodegeneration? (Neuroscience)

Eran Blacher is the 2021 winner of the NOSTER & Science Microbiome Prize for his work in illuminating the relationship between the microbiome and neurodegenerative diseases such as Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS).

The findings reveal new insights into the “gut-brain axis” and demonstrate that harnessing the microbiome and its associated metabolic pathways could provide a valuable approach to treating these and potentially other devastating neurological disorders.

Although millions of people worldwide suffer from neurodegenerative disorders, the roots of neurodegeneration remain unclear. A growing body of research consistently demonstrates that the human brain is inextricably linked to the gut microbiome, influencing brain activity in several ways. For example, small molecule metabolites produced by commensal bacteria can be absorbed into the bloodstream and reach the brain, where they can modulate the activity of brain cells, including neurons, astrocytes, and microglia.

In a mouse model, Blacher and colleagues investigated the role of the microbiome and its metabolites in ALS – a progressive neurodegenerative neuromuscular disease that affects nerve cells in the brain and spinal cord.

Blacher and the researchers depleted the microbiome of ALS-prone Sod1-Transgenic (Sod1-Tg) mice through wide-spectrum antibiotic treatment, discovering dysbiosis and microbiome-driven alterations in metabolite configuration preceding clinical ALS motor symptoms, as well as 11 distinct microbial strains correlated with disease severity.

Probiotic treatment of Sod1-Tg mice with either the gut microbe Akkermansia muciniphila or its associated metabolite, nicotinamide, improved ALS symptoms by significantly improving motor function and restored disrupted spinal cord gene expression patterns.

What’s more, in a preliminary observational study in humans, the researchers found similar, significant changes in the microbiome composition and function of ALS patients, associated with reduced nicotinamide levels in serum and cerebrospinal fluid.

“We posit that these findings are linked to our previous observations in mice and may lay the foundation of a larger clinical study in the future,” writes Blacher.

Finalists for the prize were Maria Zimmermann-Kogadeeva for her essay “Putting host-microbiota interactions in numbers,” and Erez Baruch for his essay “Gut microbiota modulation promotes response in immunotherapy-refractory melanoma patients.”

Reference: Eran Blacher, “Can microbes combat neurodegeneration?”, Science  09 Jul 2021: Vol. 373, Issue 6551, pp. 172-173. DOI: https://doi.org/10.1126/science.abi9353

Provided by AAAS

Weak Brain Waves May Warn Of Age-related Neurodegenerative Disease (Neuroscience)

People with mild cognitive impairment or Alzheimer’s disease have weaker gamma waves in their brain than healthy peers, a discovery that may lead to new ways to diagnose these conditions.

Weakened electrical signals in the brain may be an early warning sign of age-related neurodegenerative diseases such as Alzheimer’s disease, suggests a study published today in eLife.

The findings hint at new ways to identify early on patients who may have an age-related brain disease. They also provide new insights on the changes that occur in the brain as these diseases develop.

“As tools for detecting Alzheimer’s disease early are limited, there is a need to develop a reliable, non-invasive test that would enable early diagnosis,” says first author Murty Dinavahi, who was a PhD Research Scholar at the Centre for Neuroscience, Indian Institute of Science (IISc), Bengaluru, India, at the time the study was carried out, and is now a Postdoctoral Associate at the University of Maryland, US.

Previous studies in mice with a condition similar to Alzheimer’s disease had suggested that weakened gamma brain waves may be an early sign of disease. Based on these findings, Murty and colleagues conducted a community-based study on around 250 elderly subjects. They compared gamma wave activity in 12 people diagnosed with mild cognitive impairment, and five with Alzheimer’s disease, with their healthy peers.

The researchers used a technique called electroencephalography to measure electrical activity in the participants’ brains while they viewed black and white patterns on a screen. These patterns are known to induce gamma oscillations in the part of the brain that processes visual information. The team also monitored the participants’ eye movements during the experiments.

Their results showed that people who had been diagnosed with mild cognitive impairment or Alzheimer’s disease had weaker gamma waves in their brain than healthy individuals of the same age.

“We observed reductions in the strength of gamma waves in early stages of age-related cognitive decline,” Murty says. “Changes in these electrical signals could provide an early warning sign of an impending disease.” He adds that an early diagnosis could help individuals put care plans in place or allow them to begin treatments sooner.

“Our work provides a low-cost and non-invasive way to detect early signs of Alzheimer’s disease,” concludes senior author Supratim Ray, Associate Professor at the Centre for Neuroscience, IISc. “This could be useful for clinicians and scientists studying early changes that take place in the brain during age-related neurodegenerative diseases, and potentially lead to new ways to diagnose and treat these conditions.”

Reference: Dinavahi VPS Murty et al., “Stimulus-induced gamma rhythms are weaker in human elderly with Mild Cognitive Impairment and Alzheimer’s Disease”, elife, 2021. DOI: 10.7554/eLife.61666

Provided by Elife

Simple Blood Test Can Accurately Reveal Underlying Neurodegeneration (Neuroscience)

A new study of over 3000 people led by King’s College London in collaboration with Lund University, has shown for the first time that a single biomarker can accurately indicate the presence of underlying neurodegeneration in people with cognitive issues.

A new study of over 3000 people led by King’s College London in collaboration with Lund University, has shown for the first time that a single biomarker can accurately indicate the presence of underlying neurodegeneration in people with cognitive issues.

Levels of a protein called neurofilament light chain (NfL) in the blood can identify those who might have neurodegenerative diseases such as Down’s syndrome dementia, motor neuron disease (ALS) and frontotemporal dementia, when clinical symptoms are not definitive.

Published in Nature Communications and part-funded by the NIHR Maudsley Biomedical Research Centre, the research determined a set of age-related cut-off levels of NfL which could inform its potential use in primary care settings through a simple blood test.

Joint Senior Author on the study, Dr Abdul Hye from the NIHR Maudsley Biomedical Research Centre at King’s College London and South London and Maudsley NHS Foundation Trust said: ‘For the first time we have shown across a number of disorders that a single biomarker can indicate the presence of underlying neurodegeneration with excellent accuracy. Though it is not specific for any one disorder, it could help in services such as memory clinics as a rapid screening tool to identify whether memory, thinking or psychiatric problems are a result of neurodegeneration.’

Neurodegenerative diseases are debilitating conditions that result in ongoing degeneration or death of nerve cells, leading to problems in thought, attention and memory. There are currently around 850,000 people with dementia in the UK which is projected to rise to 1.6 million by 2040. In order to help identify the onset of these debilitating diseases and put in place preventative measures as early as possible there has been a drive to develop reliable and accessible biomarkers that can recognise or rule out whether the processes in the brain that are responsible for neurodegeneration are occurring.

Current biomarkers used to identify neurodegenerative disorders are taken from the fluid that surrounds the brain and spinal column (cerebrospinal fluid – CSF) which has to be extracted using an invasive procedure called lumbar puncture. Advances have been made to use biomarkers from the blood which would provide a more accessible and comfortable assessment. A central and irreversible feature in many neurodegenerative disorders is damage to the nerve fibre which results in the release of neurofilament light chain (NfL). Using ultrasensitive tests, NfL can be detected in blood at low levels and is increased in a number of disorders, unlike phosphorylated tau which is specific for Alzheimer’s disease. This means NfL can be of use in the diagnostic process of many neurodegenerative diseases most notably in this study Down’s syndrome dementia, ALS and frontotemporal dementia.

Co-author Professor Ammar Al-Chalabi from at King’s College London and co-lead of the Psychosis and Neuropsychiatry research theme at the NIHR Maudsley BRC. said

‘For neurodegenerative diseases like Alzheimer’s, Parkinson’s or motor neuron disease, a blood test to allow early diagnosis and help us monitor disease progression and response to treatment would be very helpful. Neurofilament light chain is a promising biomarker that could speed diagnosis of neurodegenerative diseases and shorten clinical trials.’

The study examined 3138 samples from King’s College London, Lund University and Alzheimer’s Disease Neuroimaging Initiative, including people with no cognitive impairment, people with neurodegenerative disorders, people with Down syndrome and people with depression. The study showed that concentrations of NfL in the blood were higher across all neurodegenerative disorders compared to those with no cognitive problems, the highest being in people with Down’s syndrome dementia, motor neuron disease and frontotemporal dementia.

The study also showed that although blood based NfL could not differentiate between all the disorders, it could provide insight into different groups within certain disorders. For example, in those with Parkinson’s a high concentration of NfL indicated atypical Parkinson’s disorder and in patients with Down syndrome, NfL levels differentiated between those with and without dementia.

Co-author Andre Strydom, Professor in Intellectual Disabilities at King’s College London said: ‘This study shows that neurofilament light chain levels were particularly increased in adults with Down syndrome who have a genetic predisposition for Alzheimer’s disease. Furthermore, we showed that those individuals with a dementia diagnosis following onset of Alzheimer’s disease had higher levels than those who did not. This suggests that the new marker could potentially be used to improve the diagnosis of Alzheimer’s in people with Down syndrome, as well as to be used as biomarker to show whether treatments are effective or not. It is exciting that all that could be needed is a simple blood test, which is better tolerated in Down syndrome individuals than brain scans.’

The study assessed age-related thresholds or cut-offs of NfL concentrations that could represent the point at which an individual would receive a diagnosis. These age-related cut-off points were 90% accurate in highlighting neurodegeneration in those over 65 years of age and 100% accurate in detecting motor neurone disease and Down syndrome dementia in the King’s College London samples, with a very similar result in the Lund samples. Importantly, NfL was able to distinguish individuals with depression from individuals with neurodegenerative disorders which commonly present with primary psychiatric disorder in the onset of disease development such as frontotemporal dementia.

Joint-Senior author Professor Oskar Hansson from Lund University said ‘Blood tests have great potential to improve the diagnosis of dementia both in specialised memory clinics and in primary care. Plasma NfL can be extremely useful in a number of clinical scenarios which can greatly inform doctors, as shown in this large study’.

Dr Hye said ‘Blood-based NfL offers a scalable and widely accessible alternative to invasive and expensive tests for dementia. It is already used as a routine assessment in some European countries such as Sweden or Netherlands, and our age-related cut-offs can provide a benchmark and quick accessible test for clinicians, to indicate neurodegeneration in people who are exhibiting problems in thinking and memory.’

Lead author Dr Nicholas Ashton from King’s College London concludes ‘We are entering an exciting period where blood tests like plasma NfL, in combination with other emerging blood biomarkers like phosphorylated tau (p-tau), are starting to give us a meaningful and non-invasive insight into brain disorders’.

‘A multicentre validation study of the diagnostic value of plasma neurofilament light’ Ashton et al is published in Nature Communications 7th June 2021 doi 10.1038/s41467-021-23620-z and will be available on this link on publication https://www.nature.com/articles/s41467-021-23620-z 

Provided by Kings College London

Scientists at IRB Barcelona Discover the Cause Of Neurodegeneration in Lafora Disease (Neuroscience)

  • The accumulation of abnormal glycogen in glial cells of the nervous system causes inflammation and degeneration of the brain.
  • This study by IRB Barcelona has been published in the journal Brain.

Lafora disease is an inherited neurodegenerative condition that initially develops with seizures in adolescence and evolves with progressive degeneration of the nervous system to death, about ten years after its onset. It is characterised by the accumulation of abnormal glycogen aggregates called Lafora bodies in the brain. There is currently no treatment for this condition, although some therapies are being tested in clinical trials.

Led by Dr. Joan Guinovart, emeritus professor of the University of Barcelona (UB) and also group leader of CIBERDEM, the Metabolic Engineering lab at IRB Barcelona has discovered that Lafora bodies that accumulate in glial cells, which are essential for the proper functioning of the nervous system, are responsible for the neurodegeneration associated with the disease.

For this study, Dr. Guinovart’s group generated a mouse model of Lafora disease, in which they prevented glycogen from accumulating in glial cells. They found that these mice did not develop neurodegeneration.

“For years, it was believed that the disease was caused by the accumulation of Lafora bodies only in neurons, but now we have shown that neurodegeneration is caused by accumulations in glial cells,” says Dr. Jordi Duran, co-director of the study.

“This discovery has important implications for the design of treatments for the disease and we now intend to investigate the mechanism by which glycogen deposits cause this damage. We will also study the possible role of this pathological mechanism in other neurodegenerative diseases,” explains Dr. Duran.  

The study also involved the laboratories led by Dr. José Antonio del Río, full professor of the UB (at the Institute for Bioengineering of Catalonia and the UB’s Institute of Neurosciences) and Professor Matthew Gentry (at the University of Kentucky).

A consortium supported by the association of affected families

This project has been developed within the framework of a global consortium for the study of Lafora disease, coordinated by the University of Kentucky in the US. In 2016, the consortium received $7.7 M from NIH (U.S. National Institutes of Health) for a period of five years. The consortium was promoted by Chelsea’s Hope, an association of families in the US affected by Lafora disease, which in 2014 brought together leading specialists to foster research into the disease.

Featured image: Lafora bodies in brain sections (hippocampus). Bodies that accumulate in the disease disappear when the ability of astrocytes to produce glycogen is removed. © IRB Barcelona

Reference article: Jordi Duran, Arnau Hervera, Kia H Markussen, Olga Varea, Iliana López-Soldado, Ramon C Sun, Jose Antonio del Río, Matthew S Gentry & Joan J Guinovart, “Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease”
Brain (2021) DOI: 10.1093/brain/awab110

Provided by IRB Barcelona

About IRB Barcelona

Created in 2005 by the Generalitat de Catalunya (Government of Catalonia) and University of Barcelona, IRB Barcelona is a Severo Ochoa Centre of Excellence, a seal that was awarded in 2011. The institute is devoted to conducting research of excellence in biomedicine and to transferring results to clinical practice, thus improving people’s quality of life, while simultaneously promoting the training of outstanding researchers, technology transfer, and public communication of science. Its 28 laboratories and eight core facilities address basic questions in biology and are orientated to diseases such as cancer, metastasis, Alzheimer’s, diabetes, and rare conditions. IRB Barcelona is an international centre that hosts 400 employees and more than 30 nationalities. It is located in the Barcelona Science Park. IRB Barcelona is a CERCA center, and a member of the Barcelona Institute of Science and Technology (BIST).

Treating Neurological Symptoms of CHARGE Syndrome (Medicine)

Discovery of a treatment that alleviates some neurological symptoms of a rare genetic disorder

CHARGE syndrome is a rare genetic disorder affecting about 1 in 10,000 newborns. It can lead to neurological and behavioural disorders for which no treatment is currently available. Dr. Kessen Patten and his team, from the Institut national de la recherche scientifique (INRS) have just discovered a compound that could alleviate these symptoms. The results of their research were published in the journal EMBO Reports.

Understanding Neurological Disorders

First described in 1979, CHARGE syndrome is caused by mutations in the CHD7 gene and is associated with neurodevelopmental disorders such as intellectual disability, attention deficit disorder with or without hyperactivity, seizures and autism spectrum disorder. Dr. Patten’s research team studied the neurological symptoms of this syndrome, which are still poorly understood.

The team developed a genetic model of zebrafish with loss of function of the CHD7 gene similar to that observed in humans. They found that the CHD7 gene regulated the type of GABAergic neurons that are essential for proper brain function.

“The loss of function of CHD7 appears to cause developmental and functional abnormalities in GABAergic neurons in the zebrafish brain that are related to the observed neurological and behavioural disorders,” explained Dr. Patten, who specializes in genetics and neurodegenerative diseases. The team also identified molecular events controlled by the CHD7 gene to explain these neurological symptoms in their genetic model. Similar findings were made using cells from patients with the disease.

Finding a Drug

The research team tested hundreds of compounds already approved for clinical use by the U.S. Food and Drug Administration. Drug screening was used to identify potential candidates for treatment–ephedrine was selected as the most therapeutic compound. “We observed therapeutic effects on both, the neurological and behavioural symptoms,” said PhD student Priyanka Jamadagni, lead author of the article. “It allowed the diseased zebrafish model to partially recover its normal functions.”

This research opens the door to new avenues for the treatment of other neurological disorders with similar neuronal imbalances, such as autism spectrum disorder and hyperactivity.

About the study

The article “Chromatin remodeler CHD7 is required for GABAergic neuron development by promoting PAQR3 expression,” by Priyanka Jamadagni, Maximilian Breuer, Kathrin Schmeisser, Tatiana Cardinal, Betelhem Kassa, J Alex Parker, Nicolas Pilon, Eric Samarut, and Shunmoogum A. Patten, was published in the journal EMBO Reports. Led by Dr. Patten, the study was conducted with the help of collaborators from the CHUM Research Centre and Université de Québec à Montréal (UQAM). The study received financial support from the CHARGE Syndrome Foundation, the Canada Foundation for Innovation (CFI), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Rare Disease Foundation. The lead author holds a doctoral scholarship from the Center of Excellence in Research on Orphan Diseases – Courtois Foundation (CERMO-FC) and a scholarship from the Armand-Frappier Foundation.

Featured image: INRS Professor Kessen Patten specializes in genetics and neurodegenerative diseases. © Christian Fleury (INRS)

Provided by INRS

About INRS

INRS is a university dedicated exclusively to graduate level research and training. Since its creation in 1969, INRS has played an active role in Quebec’s economic, social, and cultural development and is ranked first for research intensity in Quebec and in Canada. INRS is made up of four interdisciplinary research and training centres in Quebec City, Montreal, Laval, and Varennes, with expertise in strategic sectors: Eau Terre Environnement, Énergie Matériaux Télécommunications, Urbanisation Culture Société, and Armand-Frappier Santé Biotechnologie. The INRS community includes more than 1,500 students, postdoctoral fellows, faculty members, and staff.

Researchers Identify Protein Produced After Stroke that Triggers Neurodegeneration (Neuroscience)

Researchers with the Peter O’Donnell Jr. Brain Institute at UT Southwestern have identified a new protein implicated in cell death that provides a potential therapeutic target that could prevent or delay the progress of neurodegenerative diseases following a stroke.

Scientists from the departments of pathology, neurology, biochemistry, and pharmacology at UTSW have identified and named AIF3, an alternate form of the apoptosis-inducing factor (AIF), a protein that is critical for maintaining normal mitochondrial function. Once released from mitochondria, AIF triggers processes that induce a type of programmed cell death.

In a study published in the journal Molecular Neurodegeneration, the UT Southwestern team collaborated with researchers at The Johns Hopkins University School of Medicine and found that, following a stroke, the brain switches from producing AIF to producing AIF3. They also reported that stroke triggers a process known as alternative splicing, in which a portion of the instructions encoding AIF is removed, resulting in the production of AIF3. Defective splicing can cause disease, but modifying the splicing process may offer potential for new therapies.

Yingfei Wang, Ph.D. © UT Southwestern Medical Center

In both human brain tissue and mouse models developed by researchers, AIF3 levels were elevated after a stroke. In mice, the stroke-induced production of AIF3 led to severe progressive neurodegeneration, hinting at a potential mechanism for a severe side effect of stroke observed in some patients. Stroke has been recognized as the second most common cause of dementia, and it is estimated that 10 percent of stroke patients develop post-stroke neurodegeneration within one year.

The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves the combined effect of losing the original form of AIF in addition to gaining the altered AIF3, leading to both mitochondrial dysfunction and cell death.

“AIF3 splicing causes mitochondrial dysfunction and neurodegeneration,” says senior author Yingfei Wang, Ph.D., assistant professor of pathology and neurology and a member of the O’Donnell Brain Institute. “Our study provides a valuable tool to understand the role of AIF3 splicing in the brain and a potential therapeutic target to prevent or delay the progress of neurodegenerative diseases.”

The findings are important for understanding the aftereffects of stroke, which strikes nearly 800,000 U.S. residents annually. Stroke kills one person every four minutes, according to the Centers for Disease Control and Prevention (CDC), and about one in every six deaths from cardiovascular disease is attributed to stroke – with ischemic strokes accounting for about 87 percent of all cases. Leading causes of stroke include high blood pressure, high cholesterol, smoking, obesity, and diabetes. Stroke also disproportionately affects certain populations and occurs more often in men, though more women than men die from stroke. CDC figures show Black people have twice the risk of first-time stroke than white people and a higher risk of death. Hispanic populations have seen an increase in death rates since 2013, while other populations have not.

Other researchers who contributed to this study are Shuiqiao Liu, Mi Zhou, Zhi Ruan, Yanan Wang, Veena Rajaram, Andrew Lemoff, Jennifer E. Wang, Kimmo Hatanpaa, and Weibo Luo of UT Southwestern; and Calvin Chang, Masayuki Sasaki, Kalyani Nambiar, Ted M. Dawson, and Valina L. Dawson of Johns Hopkins.

This work was supported by grants from the National Institutes of Health (NIH), Darrell K Royal Research Fund, American Heart Association, NCRP Scientist Development Grant, The Welch Foundation, Cancer Prevention and Research Institute of Texas, Texas Institute for Brain Injury and Repair, UT Southwestern Medical Center Startup funds, and UT Rising STARs.

Featured image: AIF3 splicing triggers neurodegeneration and neuron loss in a mouse brain, shown in the cortex (orange and pink), hippocampus (green), and thalamus (blue). © UT Southwestern Medical Center

Reference: Liu S, Zhou M, Ruan Z, Wang Y, Chang C, Sasaki M, Rajaram V, Lemoff A, Nambiar K, Wang JE, Hatanpaa KJ, Luo W, Dawson TM, Dawson VL, Wang Y. AIF3 splicing switch triggers neurodegeneration. Mol Neurodegener. 2021 Apr 14;16(1):25. doi: 10.1186/s13024-021-00442-7. PMID: 33853653; PMCID: PMC8048367.

Provided by UT Southwestern Medical Center

Light Up Your Mind: A Novel Light-based Treatment For Neurodegenerative Diseases (Neuroscience)

Researchers review growing knowledge on the methods and applications of light therapy in treating neurodegenerative diseases

A lot about the human brain and its intricacies continue to remain a mystery. With the advancement of neurobiology, the pathogenesis of several neurodegenerative diseases (ND) has been uncovered to a certain extent along with molecular targets around which current therapies revolve. However, while the current treatments offer temporary symptomatic relief and slow down the course of the disease, they do not completely cure the condition and are often accompanied by a myriad of side effects that can impair normal daily functions of the patient.

Light stimulation has been proposed as a promising therapeutic alternative for treating various ND like Alzheimer’s disease (AD), Parkinson’s disease (PD), cognitive and sleep disorders. Light therapy consists of controlled exposure to natural daylight or artificial light of specific wavelengths. While neurologists worldwide have begun testing its use in clinical practice, less remains understood about the mechanisms behind how light affects neurological function.

Thus, in a review article now published in Chinese Medical Journal, researchers from China comprehensively summarize the growing knowledge on the mechanism of action, effectiveness, and clinical applications of LT in the treatment of ND. Neurologist and author Dr. Chun-Feng Liu explains how their work can advance our understanding of novel emerging therapies for ND. “While light therapy has been investigated in mental and sleep disorders, comprehensive knowledge on its use in neurodegenerative diseases in lacking. We therefore sought to shed light on the potential therapeutic methods and implications of light therapy,” he states.

Our body function is tuned to a circadian or day and night rhythm. The clock that controls this rhythm is housed in the hypothalamus region of the brain. The genes expressed in this region are crucial in maintaining the circadian rhythm. Thus, a malfunction of these genes can disrupt the rhythmic cycle. These defects have been associated with neurodegenerative, metabolic and sleep disorders. External stimuli such as light, physical activity and food intake can help reset the clock and restore normal circadian rhythms, thus alleviating symptoms.

Another mechanism by which the clock controls circadian rhythms is through the secretion of the melatonin (MT) hormone. MT secreted by the pineal gland in the brain is known to control sleep patterns as it is secreted in higher amounts in the night than the day. Light stimulation in this case suppresses the secretion of MT during the day time and thus reduces drowsiness.

Interestingly, different tissue and organs in the body may respond differentially to light stimulation. Furthermore, different biomolecules expressed in circulating immune cells and stem cells are sensitive to specific wavelengths of light and thus elicit different responses by promoting the secretion of neurotrophic factors that can rescue neuronal functions.

Next, the researchers go on to discuss the application of light stimulation in specific neurodegenerative disorders. In case of AD, a progressive dementia, sleep disturbance has been associated with an increased expression of biomarkers that promote disease progression. Patients with AD often experience confusion, emotional distress and hyperactivity after dusk and through the night. Preliminary clinical studies on AD mouse models as well as patients with AD suggest that light stimulation helps restore memory and cognition and decreases the burden of the pathogenic amyloid-β protein in the brain. Furthermore, LT has been shown to improve sleep quality and duration in patients with sleep disorders while bright environments help reduce anxiety and aggressive behaviors in patients with dementia.

In case of PD, patients suffer from motor impairment, tremors and posture imbalance and also display non-motor symptoms such as insomnia, depression and fatigue that can collectively impair their quality of life. While LT has been shown to decrease non-motor symptoms to some extent, evidences on its direct benefits towards motor-function however are limited.

The use of LT in other neurodegenerative disorders is currently at preclinical stages and needs to be pursued further. Overall, LT offers a safe and cost-effective alternative for treatment of ND. Additional studies and large scale clinical trials in this direction can help establish its effectiveness as a potential therapeutic strategy.

Explaining the long term clinical applications of LT, Dr. Liu says, “The light box or light therapy lamp will help improve the sleep quality of patients with sleep disorders. Light stimulation will also likely have therapeutic effects on neurodegenerative diseases and seasonal depression. Further studies are needed to elucidate its effectiveness.”

This review not only advances our understanding on how LT functions in resetting the circadian rhythm and associated neurological symptoms but also highlights its applications in routine clinical practice.

Featured image: Light therapy can reset disturbed circadian rhythms in patients with sleep disorders and neurodegenerative diseases and thus alleviate symptoms © Gerd Altmann from Pixabay


  • Titles of original papers: Light therapy: a new option for neurodegenerative diseases
  • Journal: Chinese Medical Journal
  • DOI: 10.1097/CM9.0000000000001301

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