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Tag: Neuron

  • Eye movement reflex reveals genetic association with autism

    Eye movement reflex reveals genetic association with autism

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    Scientists at UC San Francisco may have discovered a new way to test for autism by measuring how children’s eyes move when they turn their heads.

    They found that kids who carry a variant of a gene that is associated with severe autism are hypersensitive to this motion.

    The gene, SCN2A, makes an ion channel that is found throughout the brain, including the region that coordinates movement, called the cerebellum. Ion channels allow electrical charges in and out of cells and are fundamental to how they function. Several variants of this gene are also associated with severe epilepsy and intellectual disability. 

    The researchers found that children with these variants have an unusual form of the reflex that stabilizes the gaze while the head is moving, called the vestibulo-ocular reflex (VOR). In children with autism, it seems to go overboard, and this can be measured with a simple eye-tracking device.

    The discovery could help to advance research on autism, which affects 1 out of every 36 children in the United States. And it could help to diagnose kids earlier and faster with a method that only requires them to don a helmet and sit in a chair.

    “We can measure it in kids with autism who are non-verbal or can’t or don’t want to follow instructions,” said Kevin Bender, PhD, a professor in the UCSF Weill Institute for Neurosciences and co-senior author of the study, which appears Feb. 26 in Neuron. “This could be a game-changer in both the clinic and the lab.” 

    A telltale sign of autism in an eye reflex 

    Of the hundreds of gene mutations associated with autism, variants of the SCN2A gene are among the most common.

    Since autism affects social communication, ion channel experts like Bender had focused on the frontal lobe of the brain, which governs language and social skills in people. But mice with an autism-associated variant of the SCN2A gene did not display marked behavioral differences associated with this brain region.

    Chenyu Wang, a UCSF graduate student in Bender’s lab and first author of the study, decided to look at what the SCN2A variant was doing in the mouse cerebellum. Guy Bouvier, PhD, a cerebellum expert at UCSF and co-senior author of the paper, already had the equipment needed to test behaviors influenced by the cerebellum, like the VOR. 

    The VOR is easy to provoke. Shake your head and your eyes will stay roughly centered. In mice with the SCN2A variant, however, the researchers discovered that this reflex was unusually sensitive. When these mice were rotated in one direction, their eyes compensated perfectly, rotating in the opposite direction. 

    But this increased sensitivity came at a cost. Normally, neural circuits in the cerebellum can refine the reflex when needed, for example to enable the eyes to focus on a moving object while the head is also moving. In SCN2A mice, however, these circuits got stuck, making the reflex rigid. 

    A mouse result translates nearly perfectly to kids with autism 

    Wang and Bender had uncovered something rare: a behavior that arose from a variant to the SCN2A gene that was easy to measure in mice. But would it work in people?

    They decided to test it with an eye-tracking camera mounted on a helmet. It was a “shot in the dark,” Wang said, given that the two scientists had never conducted a study in humans. 

    Bender asked several families from the FamilieSCN2A Foundation, the major family advocacy group for children with SCN2A variants in the US, to participate. Five children with SCN2A autism and eleven of their neurotypical siblings volunteered.

    Wang and Bender took turns rotating the children to the left and right in an office chair to the beat of a metronome. The VOR was hypersensitive in the children with autism, but not in their neurotypical siblings.

    The scientists could tell which children had autism just by measuring how much their eyes moved in response to their head rotation. 

    A CRISPR cure in mice

     The scientists also wanted to see if they could restore the normal eye reflex in the mice with a CRISPR-based technology that restored SCN2A gene expression in the cerebellum. 

    When they treated 30-day-old SCN2A mice – equivalent to late adolescence in humans – their VOR became less rigid but was still unusually sensitive to body motion. But when they treated 3-day-old SCN2A mice – early childhood in humans – their eye reflexes were completely normal. 

    These first results, using this reflex as our proxy for autism, point to an early window for future therapies that get the developing brain back on track.”

    Chenyu Wang, UCSF graduate student

    It’s too early to say whether such an approach might someday be used to directly treat autism. But the eye reflex test, on its own, could clear the way to more expedient autism diagnosis for kids today, saving families from long diagnostic odysseys.

    “If this sort of assessment works in our hands, with kids with profound, nonverbal autism, there really is hope it could be more widely adopted,” Bender said.

    Source:

    University of California – San Francisco

    Journal reference:

    Wang, C., et al. (2024). Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD. Neuron. doi.org/10.1016/j.neuron.2024.01.029.

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  • How cell types and location influence Parkinson’s disease

    How cell types and location influence Parkinson’s disease

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    In a recent study published in Cell Reports, researchers conducted a single-cell spatial transcriptome analysis on murine brain expression in age and disease using a Parkinson’s disease (PD) transgenic model, focusing on dopaminergic neurons (DA) spanning 29 cell types.

    Study: Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Image Credit: solarseven/Shutterstock.comStudy: Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease. Image Credit: solarseven/Shutterstock.com

    Background

    The spatially structured brain contains various cells, each with a distinct purpose. PD is a neurodegenerative condition characterized by DA loss and alpha-synuclein buildup due to overexpression via locus multiplication.

    Single-cell ribonucleic acid sequencing (RNS-seq) has improved the knowledge of cell-based expression in organs such as the brain, but current methods fail to attain high-throughput resolution. Fluorescent in situ hybridization (FISH) technologies provide higher sensitivity at an individual level.

    About the study

    In the present study, researchers performed single-cell spatial transcriptomic and translatomic profiling of DA to find markers for healthy and aged cells.

    The researchers crossed Rosa26fsTRAP::DATIREScre (DAT-TRAP) mice with SNCA-OVX mice to enable DA messenger RNA (mRNA) capture in a PD model.

    The mice were aged to 18 months to assess the influence of human ⍺-synuclein overexpression and aging on dopaminergic neuron genetic expression and study the effect of healthy and Parkinsonian aging.

    The researchers created a single-cell-level spatial transcriptomic map of gene expression in the adult mouse brain and a high-fidelity translatome-level profile of DA neuron expression.

    They analyzed stereo-seq arrays with special transcript maps. They converted the transcript expression maps to segmented individual cells, identifying 29 types of cells, including astrocytes and inhibitory cortical neurons, in 18 brain slices.

    The team filtered the segmented cells by transcriptome size and complexity and analyzed spatially distinct cortex, hippocampus, and thalamus populations. They also examined the ventral midbrain and striatum to enrich transcripts confined to the cell body and putative axon.

    They used data from gene enrichment and genome-wide association studies (GWAS) to identify potential disease-causing genes.

    They evaluated each cell’s location and compared DA neuronal gene expression in various cells.

    The researchers examined enhanced green fluorescent protein (eGFP)-tagged ribosomes in DAT-expressing cells and confirmed eGFP colocalization with tyrosine hydroxylase (TH), a DA neuronal marker.

    They split cells from stereo-seq brain slices, filtering them based on detected genes, and performed Uniform Manifold Approximation and Projection (UMAP) analysis.

    They also performed short- and long-read RNA sequencing of the translating mRNA collected by TRAP and used stereo-sequencing and TRAP data to rank prospective genes for inquiry into sporadic PD.

    The researchers demonstrated specific enrichment of DA marker genes and depletion of marker genes of other neighboring cell types in DAT-TRAP mRNA.

    They confirmed specific calcium-sensing receptor (CASR) protein expression in mouse ventral midbrain neurons and investigated CASR expression in human-induced pluripotent stem cell-derived DA neurons. They also examined age-related gene variations in cells revealed by stereo-seq.

    Results

    The team studied PD in young and aged brains to identify genes having spatially varying expression in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and particular markers such as copine-7 (Cpne7) and Solute carrier family 10 member 4 (Slc10a4) genes.

    They also detected splice variants unique to DA. They demonstrated ways of using TRAP and stereo-sequencing expression specificity measurements to identify potentially relevant genes from GWAS areas, indicating that CASR regulates intracellular DA neuronal calcium.

    The findings demonstrated substantia nigra-specific DA neuronal loss and increased microglial activation with age. They highlighted aging- and disease-associated genetic alterations in various cells, including dopaminergic neurons, across many PD-related pathways.

    Stereo-seq detected expression alterations caused by aging and illness across different cell types, loss of nigral DA neurons, and the neuroinflammatory expansion of microglia.

    Pathway enrichment research revealed that various biological processes were altered, including axon ensheathment, synaptic transmission modulation, intracellular calcium ion homeostasis, and catecholamine secretion control.

    The team extracted 355,307 transcriptomes of high quality with spatial coordinate details from 18 murine brains, identifying a total of 14,494 genes.

    They observed synaptosomal-associated protein, 25kDa (Snap25) expression, and structured localization in places like the thalamus or hippocampus differentiated neurons from glia.

    They also examined neuronal cells in the CA1 region, CA3 region, subiculum, and dentate gyrus in the hippocampus region or gamma-aminobutyric acid (GABA)-releasing nuclei in the midbrain.  

    Marker expression enabled oligodendrocyte, astrocyte, microglia, and erythrocyte identification. In DAT-TRAP samples, classical markers of dopaminergic neurons showed significant enrichment, whereas those of other cell types decreased in the ventral midbrain.

    Conclusion

    Overall, the study identified 29 unique brain cell types by examining variations in spatial gene expression linked to aging and illness. The stereo-seq data indicated differences in transcript use across more than a thousand genes.

    There were 817 occurrences of alternative splicing, suggesting that more genes were being translated than gene-level count data showed. The study also discovered an age-dependent drop in SN DA neuron cell number, which supports earlier findings.

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  • Restoring brain pathways to fight opioid addiction

    Restoring brain pathways to fight opioid addiction

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    Medical University of South Carolina scientists report in Neuron that they have uncovered a way to restore an opioid-weakened brain pathway in a preclinical model.

    With funding from the National Institute on Drug Abuse, part of the National Institutes of Health, the MUSC research team, led by neuroscientist James Otis, Ph.D., used advanced neuroscience tools to return a pathway between the thalamus and basal ganglia to healthy functioning in mice. As a result, this restoration prevented mice that were opioid-dependent from seeking or self-administering heroin. Results also suggested that sustained opioid use was the cause of this weakened pathway, rather than being caused by it.

    Our study is the first showing that this pathway, associated with the capability of stopping behavior, can be ‘rescued’ after being weakened by opioid use.”


    James Otis, Ph.D., Neuroscientist 

    Otis was surprised that not only could this brain pathway be returned to healthy functioning, but that its recovery prevented relapse.

    “When we brought this brain circuit back to what we think of as a healthy state, we were excited to see that it could inhibit behaviors such as relapse,” said Otis.

    This pathway of neurons identified by Otis’ team is critical for controlling or stopping behavior – also referred to as behavioral control. Difficulty stopping is a hallmark feature of many neuropsychiatric disorders, including substance use disorders. The capacity to stop is a critical skill in recovering from drug dependence and avoiding relapse.

    Studies have shown that people with substance use disorders find it more difficult to stop behavior, he explained. In previous studies, they took longer to pause behavioral tasks than those without a history of substance use.

    Difficulty stopping is a key reason why people with substance use disorders may continue to use substances despite negative consequences or despite their desire to stop. Restoring behavioral control could improve their ability to stop such behaviors and remain drug abstinent.

    Researchers have identified pathways in the brain that influence our capacity to stop different behaviors. For example, our brains can stop motor movement when two regions of the brain – the prefrontal cortex and basal ganglia – talk to one another. The prefrontal cortex makes the decision to stop and sends this message to the basal ganglia. The basal ganglia then prevents the movement. The communication between these areas of the brain has been shown to be disrupted in people with substance use disorders, helping to explain the challenges they face with this skill.

    Expanding on this research, Otis and his team identified a new pathway of neurons in mice involved with stopping behavior. In a previous study, his team found that this series of neurons, beginning in the thalamus, similarly communicated with the basal ganglia to control movement.

    This study reported in Neuron helps to resolve a long-standing chicken-or-egg debate about the relationship between difficulty stopping behavior and substance use disorder. Does an impaired capacity to stop increase the likelihood that someone will later develop a substance use disorder? Or does repeated drug use weaken the parts of the brain involved with this ability?

    “We wanted to know more about how opioid use influences these neurons, or if instead these neurons are already impaired in those who are vulnerable to future opioid addiction,” Otis explained.

    Findings from this research strongly suggest that the weakening of this pathway happens because of opioid use, rather than being a cause of opioid use. After two weeks of opioid use by the mice, Otis and his team observed that this pathway became half as strong as it was prior to drug use. 

    The next step is to see if these results can be repeated with substances such as alcohol, methamphetamine, amphetamine and cocaine.

    The experimental techniques used to restore this brain circuit in a preclinical model are not suitable for human studies. However, Otis can envision that future drug treatments could rehabilitate brain functioning associated with drug use.

    “The goal of addiction treatment should be to recover healthy brain circuitry, rather than just prevent relapse or prevent the symptoms of addiction,” said Otis.

    Source:

    Medical University of South Carolina

    Journal reference:

    Paniccia, J. E., et al. (2023). Restoration of a paraventricular thalamo-accumbal behavioral suppression circuit prevents reinstatement of heroin seeking. Neuron. doi.org/10.1016/j.neuron.2023.11.024.

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  • Study provides evidence that antidepressant use in pregnancy affects child’s brain development

    Study provides evidence that antidepressant use in pregnancy affects child’s brain development

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    The prefrontal cortex (PFC) is an important brain region with respect to behavioral regulation. Aberrations in serotonin (5-HT) during early development have been reported to be associated with behavioral dysregulations over the long term, but how this works is still unclear.

    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com
    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com

    A new study published in Nature Communications explored synapse maturation in the PFC of mice when exposed to 5-HT, shedding light on the link between the chemical and future behavioral changes.

    Researchers from the University of Colorado Anschutz Medical Campus demonstrated a direct link between antidepressant use during pregnancy, particularly fluoxetine found in medications like Prozac and Sarafem, and altered development of the prefrontal cortex in children, as well as subsequent mental health risks.

    Background

    The brain has over a billion neurons, with equal numbers of other cells linked in intricate and interwoven networks. These require exquisitely precise chemical regulation to develop correctly so as to provide the substrate for communication between themselves and the formation of neuronal pathways.

    5-HT is among the first neurochemicals to be detected, being found at peak levels two years after birth in humans. In mice, it peaks during the first week after birth. This period coincides with the time when excitatory synapses mature following experience-driven activity.

    Various causes of alteration in 5-HT are known, including maternal malnutrition, maternal abuse, varying levels of dietary tryptophan (the substrate for 5-HT formation), and the presence of chemicals that regulate the uptake or degradation of 5-HT.

    An example of the latter is the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These can readily cross the placenta or enter breast milk, becoming available to the offspring during a critical period of brain development.

    Such imbalances in 5-HT levels at this period have been linked to a higher chance of neurodevelopmental disorders, including autism spectrum disorder (ASD), as well as permanent behavioral changes. The PFC is involved in cognitive processes that facilitate social interaction and is lavishly supplied with neurons that release 5-HT.

    Excitatory synapses are fundamental to the formation of neural circuits. They need to mature and stabilize for this to happen, with the primary sites of action of the neurotransmitter released at the synapse being the dendritic spines of the post-synaptic neuron. These bear multiple receptor types for 5-HT, with 5-HT2A and 5-HT7 being especially abundant in early infancy.

    When these are activated, excitatory cascades are activated via the coupled Gαq proteins. Higher levels of 5-HT signaling increase the dendritic spine plasticity. The current study looked at targeted 5-HT signaling at the level of neural circuits and individual excitatory synapses, seeking to identify the mode of regulation. 

    What did the study show?

    The scientists found that 5-HT is crucial for the normal development of excitatory synapses on the pyramidal neurons within layer 2/3 of the PFC during early development. With 5-HT inhibition, both spine density and maturation were reduced significantly within the PFC, though spine size remained intact. The converse was also true, with increased density, especially of large spines, but with normal size and morphology.

    Apart from these anatomical changes, 5-HT signaling causes structural long-term potentiation of dendritic spines on these neurons during this developmental window independent of excitatory stimulation. This effect, namely, the enlargement of small and medium spines, did not appear to depend on the activity of glutamate.

    Not only was it specific for the pattern of 5-HT stimulation, but also it was not observed at later stages or in pyramidal neurons. In addition, it occurred only in the presence of post-synaptic 5-HT2A and 5-HT7 signaling. This suggests that the underlying mechanism is 5-HT7 receptor-mediated influx of extracellular calcium ions, leading to 5-HT2A receptor-induced activation of PKC.

    Functional long-term potentiation of these receptors was also observed in response to 5-HT release, again via 5-HT2A and 5-HT7 receptor signaling. That is, stronger post-synaptic excitatory currents were measured following 5-HTergic stimulation.

    Individual dendritic spines newly formed on these neurons in the PFC were more likely to survive, indicating greater long-term stabilization following Gαs coupled 5-HT7 receptor signaling. This is important as it leads to increased spine density. Again, this effect, linked to long-term potentiation, is independent of glutamate release or structural potentiation and does not appear to occur with 5-HT2A receptor stimulation.

    Significantly, early research shows a risk of behavioral deficits and neurodevelopmental disorders with early fluoxetine exposure. In the present study, the use of fluoxetine, an SSRI that increases 5-HT levels in the synaptic cleft in younger but not older pups, led to increased spine density but not spine size. This was mediated by 5-HT2AR and 5-HT7R signaling in the PFC.

    What are the implications?

    The findings of this study indicate that 5-HT signaling plays a key role in excitatory synapse maturation during early development of the PFC circuits, regulating spine maturation and function. The effect is structural and functional potentiation of excitatory synapses of layer 2/3 pyramidal neurons in the PFC at a specific age and with a specific pattern of stimulation.

    The results also suggest a direct effect of 5-HT on maturation rather than via changes in excitability, but further work is required to rule out glutamatergic involvement in synaptic plasticity secondary to 5-HT signaling completely.

    The researchers propose that nascent spines are stabilized by 5-HT7 receptor activation via voltage-gated calcium channel opening, leading to the entry of calcium into the neuron. However, as they mature, both 5-HT7 and 5-HT2A receptors lead to synapse maturation via PKC activation, which further enhances extracellular calcium ion influx.

    Moreover, 5-HT receptor-mediated synaptic plasticity occurs in the first two weeks in mice. Further research will be required to demonstrate what receptor classes are involved at later stages. Again, increased excitatory post-synaptic current strength without spine size alterations needs to be explained.

    These findings may help treat patients who have been exposed to drugs like fluoxetine during early development, as this is a commonly prescribed drug during pregnancy. Moreover, it may be possible to treat individuals with aberrations in 5-HT receptor-mediated plasticity during this key period by selective inhibition of 5-HT receptors in certain brain regions or certain types of neurons.

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  • Immune system in the blood of Alzheimer’s patients found to be epigenetically altered

    Immune system in the blood of Alzheimer’s patients found to be epigenetically altered

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    A new Northwestern Medicine study has found the immune system in the blood of Alzheimer’s patients is epigenetically altered. That means the patients’ behavior or environment has caused changes that affect the way their genes work. 

    Many of these altered immune genes are the same ones that increase an individual’s risk for Alzheimer’s. Northwestern scientists theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors.

    It is possible that these findings implicate the peripheral immune response in Alzheimer’s disease risk. We haven’t yet untangled whether these changes are reflective of brain pathology or whether they precipitate the disease.” 


    David Gate, lead investigator, assistant professor of neurology at Northwestern University Feinberg School of Medicine

    The study was published Feb. 9 in Neuron.

    Previous research showed that many of the mutated genes putting a person at higher risk for Alzheimer’s are in the immune system. But scientists primarily studied the central immune system in the brain because Alzheimer’s is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.

    Gate decided to study the blood. He and colleagues discovered every immune cell type in Alzheimer’s patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open -; or exposed -; the cells’ genome is vulnerable to alterations.

    Then, Gate examined which genes are more open in these immune cells. He discovered that a receptor -; CXCR3 -; on the T cells was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally enter the brain because they can cause inflammation. 

    “The brain is emitting a signal that it is damaged, and the T cells are homing to that signal by their antenna, CXCR3,” Gate said. 

    “T cells can be very toxic in the brain, but we also don’t know if these cells might be attempting to repair the damage in the brain,” Gate said.

    Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.

    “Altogether, these findings indicate that immune function in Alzheimer’s patients is significantly altered,” Gate said. “It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes.”

    The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. Next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets.

    Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst.

    The title of the article is “Epigenetic dysregulation in Alzheimer’s disease peripheral immunity.”

    The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging grant AG078713, both of the National Institutes of Health, Bright Focus Foundation, Alzheimer’s Association and Cure Alzheimer’s Fund.

    Source:

    Journal reference:

    Ramakrishnan, A., et al. (2024) Epigenetic dysregulation in Alzheimer’s disease peripheral immunity. Neuron. doi.org/10.1016/j.neuron.2024.01.013.

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  • New drug targets key mechanism in ALS, protects motor neurons

    New drug targets key mechanism in ALS, protects motor neurons

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    A new pharmacological inhibitor can intervene in a central cell death mechanism that is responsible for the death of motor neurons and hence important for the progression of the motor neuron disease amyotrophic lateral sclerosis (ALS). A research team led by Prof. Dr Hilmar Bading, neurobiologist at Heidelberg University, examined a neuroprotective molecule that belongs to a novel drug class. It is able to inhibit the interactions of certain proteins and has been successfully tested in a mouse model of ALS and in brain organoids of ALS patients. “On the long road to an effective treatment for ALS patients, these findings from basic research may represent a significant step forward,” says Prof. Bading.

    ALS is a degenerative disease of the nervous system particularly affecting and harmful to motor neurons. As the disease progresses, the nerve cells controlling voluntary muscle movement die. That leads to a progressive wasting of the muscles responsible for moving and speaking, but also for eating and breathing. To date, says Prof. Bading, there is no effective drug treatment for ALS patients, who in most cases die within two to five years after the diagnosis.

    The FP802 molecule the Heidelberg scientists used in the study belongs to a new pharmacological class of drugs. These are “TwinF interface inhibitors”, which were discovered by Prof. Bading and his team at the Interdisciplinary Center for Neurosciences (IZN) of Heidelberg University. These inhibitors disrupt the physical interactions of two ion channel proteins, with the names NMDA receptor and TRPM4, which, due to a so-called protein pocket named “TwinF” by the Heidelberg scientists, form a protein-protein complex.

    NMDA receptors are found on the cell surface of nerve cells and are present both in the synapses, the contact points between the nerve cells, and outside these contact points. They are activated by a biochemical messenger substance, the neurotransmitter glutamate. The stimulation of synaptic NMDA receptors in the brain contributes to learning and memory processes, as well as to protecting nerve cells. Outside the synapses, however, the activation of these receptors leads to a damaging of nerve cells and to their death. The team around Hilmar Bading investigated the reasons for this in a prior study. They found out that TRPM4 confers toxic properties to the extrasynaptic NMDA receptors in the brain. Together these two proteins form a “death complex”, which also plays a role in ALS.

    The neuroprotective molecule FP802 binds to the TwinF protein pocket of TRPM4, blocks the contact areas of the interacting proteins, and thereby disrupts the fatal complex of NMDA receptors and TRPM4. The Heidelberg scientists have studied this new drug principle using an ALS mouse model as well as brain organoids of ALS patients. “With this completely new therapeutic concept in combating neurodegenerative diseases we were able to achieve remarkable outcomes,” says Prof. Bading. The scientist explains that it was possible to prevent cell death and hence the loss of spinal motor neurons of mice by giving them the neuroprotectant. This treatment improved their motor abilities, mitigated the progression of the disease and extended the lifespan of the animals.

    The discovery of this new pharmacological class of drugs opens up a promising path for fighting ALS. A long-term goal is to develop TwinF interface inhibitors for use in patients.”


    Hilmar Bading, Interdisciplinary Center for Neurosciences (IZN) of Heidelberg University

    In close cooperation with the startup FundaMental Pharma, a Biotech offshoot of the IZN Department of Neurobiology, the molecule FP802 is to be optimised for use in humans in the coming years and tested for efficacy in clinical trials. Dr Jing Yan, who was involved in the latest study, recently joined FundaMental Pharma in order to accelerate the further development of FP802.

    The research was funded by the German Research Foundation, the European Research Council and the Alexander von Humboldt Foundation. The results were published in the journal “Cell Reports Medicine”.

    Source:

    Journal reference:

    Yan, J., et al. (2024). TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2024.101413.

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  • Protein may hold key to restoring treatment response in drug-resistant neuroendocrine prostate cancer

    Protein may hold key to restoring treatment response in drug-resistant neuroendocrine prostate cancer

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    It may be possible to restore drug-resistant neuroendocrine prostate cancer to a state that responds to treatment by depletion of a certain protein in cancer cells. A recent study by the University of Eastern Finland found that this protein, DPYSL5, is expressed in neuroendocrine prostate cancer.

    Prostate cancer is the most common cancer in men, and the second most common cause of cancer death in Western countries. The growth of prostate cancer often depends on androgens, and the effect of androgens is sought to be reduced by drug therapy, especially in metastatic prostate cancer. However, cancer cells can become resistant to drugs, resulting in castration-resistant prostate cancer.

    Second-generation antiandrogens, which are drugs that inhibit the activity of the androgen receptor, have been developed as a treatment alternative for castration-resistant prostate cancer. Unfortunately, recent studies have shown that about one in four castration-resistant prostate cancers develop into what is known as treatment-induced neuroendocrine cancer, which is aggressive and typically leads to death within a year of the diagnosis. Neuroendocrine prostate cancer cells usually do not have androgen receptors, and currently no treatment is available for this group of patients.

    A protein affecting neuroplasticity promotes the development of neuroendocrine prostate cancer

    At the University of Eastern Finland, the Ketola Lab led by Academy Research Fellow Kirsi Ketola explores the differentiation, plasticity and development of drug resistance in cancer cells.

    In the new study researchers at the Ketola Lab discovered a potential new target for drug development in neuroendocrine prostate cancer. The protein, DPYSL5, is expressed especially in this cancer type and could therefore be a suitable target for drug therapy.

    The Ketola Lab collaborated with the University of British Columbia in Canada, utilising the university’s extensive collection of neuroendocrine prostate cancer patient tumor samples to verify the expression of the DPYSL5 protein in these samples.

    Normally, the DPYSL5 protein regulates the development of neurons in the brain and is not expressed in other parts of the body. However, the researchers now found that antiandrogen treatment caused the DPYSL5 protein to be expressed in prostate cancer cells. As a result, these cells acquired stem cell-like and neuron-like properties observed in neuroendocrine prostate cancer cells.

    DPYSL5 promoted cell transformation by activating the PRC2 complex, which caused cancer cells to go into a stem cell-like state. DPYSL5 also caused cancer cells to form extensions similar to those found in neurons, which helped them to invade the surrounding tissue. However, depletion of DPYSL5 inactivated the PRC2 complex, prevented the formation of neuron-like extensions, and restored cells to a state where antiandrogen treatment was once again effective preventing cell division.

    The findings can be used for the development of new cancer drugs.

    Next, we will be using novel imaging methods available at our Cell and Tissue Imaging Unit to screen drugs that inhibit the function of DPYSL5.”


    Kirsi Ketola, Academy Research Fellow

    Published in Nature Communications Biology, the study was funded by the Research Council of Finland, the Sigrid Jusélius Foundation, the Finnish Cultural Foundation, the Finnish Cultural Foundation North Savo Regional Fund, and the Cancer Foundation of Finland.

    Source:

    University of Eastern Finland

    Journal reference:

    Kaarijärvi, R., et al. (2024). DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2. Communications Biology. doi.org/10.1038/s42003-023-05741-x.

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