Neuroscience
Abstract
Multiple sclerosis is characterized by CNS infiltration of auto-reactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ anti-neural T cells in the irreversible neurodegeneration that underlies progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell-mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer-based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell-mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.
Authors
Ethan M. Grund, Benjamin D.S. Clarkson, Susanna Pucci, Maria S. Westphal, Carolina Muniz Partida, Sara A. Muhammad, Charles L. Howe
Abstract
Loss-of-function mutations in the GBA1 gene are a prevalent risk factor for Parkinson’s disease (PD). Defining features are Lewy bodies that can be rich in α-synuclein (αS), vesicle- and other lipid membranes coupled with striatal dopamine loss and progressive motor dysfunction. Of these, lipid abnormalities are the least understood. An altered lipid metabolism in PD patient-derived neurons, carrying mutations in either GBA1, encoding for glucocerebrosidase, or αS can shift the physiological αS tetramer-monomer (T:M) equilibrium, resulting in PD phenotypes. We previously reported inhibition of stearoyl-CoA desaturase (SCD), the rate-limiting enzyme for fatty acid desaturation, stabilized αS tetramers and improved motor deficits in αS mice. Here we show that mutant GBA-PD cultured neurons have increased SCD products (monounsaturated fatty acids, MUFAS) and reduced αS T:M ratios that were improved by inhibiting SCD. Oral treatment of symptomatic L444P- and E326K Gba1 mutant mice with 5b also improved the αS T:M homeostasis and dopaminergic striatal integrity. Moreover, SCD inhibition normalized GCase maturation and dampened lysosomal and lipid-rich clustering, key features of neuropathology in GBA-PD. In conclusion, this study supports brain MUFA metabolism links GBA1 genotype and wildtype αS homeostasis to downstream neuronal and behavioral impairments, identifying SCD as a therapeutic target for GBA-PD.
Authors
Silke Nuber, Harrison Hsiang, Esra'a Keewan, Tim E. Moors, Sydney J. Reitz, Anupama Tiwari, Gary P. H. Ho, Elena Su, Wolf Hahn, Marie-Alexandre Adom, Riddhima Pathak, Matthew Blizzard, Sangjune Kim, Han Seok Ko, Xiaoqun Zhang, Per Svenningsson, Dennis J. Selkoe, Saranna Fanning
Abstract
Oxytocin plays a key role in reproductive physiology but has recently garnered interest for its involvement in modulating feeding behavior. The vagus nerve contributes to feeding behavior control, as well as other gastrointestinal functions. Oxytocin receptors (OTR) are expressed on the vagus, but their role is poorly understood. Herein, we evaluated the contribution of the vagal OTR to food intake and body weight control in male and female rats. Virogenetic knockdown of vagal OTR resulted in reduced body weight and food intake in male rats. Loss of OTR in the vagus also resulted in suppressed locomotor activity in males but hyperactivity in females. Importantly, rats with vagal OTR knockdown, but not controls, exhibited a significantly elevated mortality rate starting 4 weeks after knockdown, with males being disproportionately affected. Mortality followed large eating bouts and was accompanied by abnormal presence of food in the mouth and esophagus, suggesting death by aspiration or food in the airways and suggesting a crucial role of vagal OTR in upper gastrointestinal tract motility. Furthermore, in vivo experiments revealed impaired esophageal transit. Ex vivo findings indicated oxytocin’s contribution to lower esophageal sphincter contraction. Our findings demonstrated a critical role for the oxytocin system: essential function of vagal OTR for esophageal transit and swallowing.
Authors
Mohammed Asker, Jean-Philippe Krieger, Ivana Maric, Emre Bedel, Jenny Steen, Stina Börchers, Yuxiang Wen, Francesco Longo, Patrik Aronsson, Michael Winder, Robert P. Doyle, Matthew R. Hayes, Karolina P. Skibicka
Abstract
JAK inhibitors (JAKi) are widely used anti-inflammatory drugs. Recent data suggest JAKi have superior effects on pain reduction in rheumatoid arthritis (RA). However, the underlying mechanisms for this observation are not fully understood. We investigated whether JAKi can act directly on human sensory neurons. We analysed RNA sequencing datasets of sensory neurons and found they expressed JAK1 and STAT3. Addition of cell-free RA synovial fluid to human induced pluripotent stem cell (iPSC)-derived sensory neurons led to phosphorylation of STAT3 (pSTAT3), which was completely blocked by the JAKi tofacitinib. Compared to paired serum, RA synovial fluid was enriched for the STAT3 signalling cytokines IL-6, IL-11, LIF, IFN-alpha and IFN-beta, with their requisite receptors present in peripheral nerves post-mortem. Accordingly, these recombinant cytokines induced pSTAT3 in iPSC-derived sensory neurons. Furthermore, IL-6+sIL-6R and LIF upregulated expression of pain-relevant genes with STAT3-binding sites, an effect which was blocked by tofacitinib. LIF also induced neuronal sensitisation, highlighting this molecule as a putative pain mediator. Finally, over time, tofacitinib reduced the firing rate of sensory neurons stimulated with RA synovial fluid. Together, these data indicate that JAKi can act directly on human sensory neurons, providing a potential mechanistic explanation for their suggested superior analgesic properties.
Authors
Yuening Li, Elizabeth H. Gray, Rosie Ross, Irene Zebochin, Amy Lock, Laura Fedele, Louisa Janice Kamajaya, Rebecca J. Marrow, Sarah Ryan, Pascal Röderer, Oliver Brüstle, Susan John, Franziska Denk, Leonie S. Taams
Abstract
Background: Traffic-related air pollution (TRAP) is a risk factor for Alzheimer disease (AD), where unresolved brain inflammation has been linked to deficits in the levels of free lipid mediators that enable the resolution of inflammation. It is unknown whether these deficits are due to reductions in esterified lipid pools, the main source of free bioactive pro-resolving lipids in the brain, and whether they are related AD pathophysiology. Methods: This unknown was tested by measuring brain esterified lipid mediators and pathogenic markers of AD in TgF344-AD and wildtype (WT) male and female rats exposed to filtered air or TRAP for 14 months, and in human postmortem pre-frontal cortex of individuals with or without AD. Results: Significant reductions in pro-resolving lipid mediators esterified to neutral lipids and/or phospholipids were seen in AD and TRAP-exposed female rats, where levels were associated with inflammation, synaptic loss and impaired glucose metabolism. Lower esterified pro-resolving lipid mediator concentrations were associated with older age in pre-frontal cortex of humans with AD. Conclusion: Impaired resolution in AD is due to depletion of esterified pro-resolving lipid pools that supply the brain with free bioactive mediators involved in inflammation resolution. TRAP exposure alters the same esterified resolution pathways, reflecting convergent mechanisms underlying AD.
Authors
Ameer Y. Taha, Qing Shen, Yurika Otoki, Nuanyi Liang, Kelley T. Patten, Anthony E. Valenzuela, Christopher D. Wallis, Douglas J. Rowland, Abhijit J. Chaudhari, Keith J. Bein, Anthony S. Wexler, Lee-Way Jin, Brittany N. Dugger, Danielle J. Harvey, Pamela J. Lein
Abstract
PCSK9 induces the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9, notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the impact of PCSK9 on the peripheral nervous system remains unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy, characterized by reduced thermal and mechanical pain sensations. PCSK9 deficient mice also presented with skin structural changes, including a reduction in the number of nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, the peripheral nerves of PCSK9-deficient mice showed an upregulation of CD36, a fatty acid transporter, which correlated with increased nerve lipid content, structural mitochondrial abnormalities, and acylcarnitine accumulation. Our findings demonstrate that PCSK9 plays a critical role in peripheral nerves by regulating lipid homeostasis and its deficiency results in symptoms related to peripheral neuropathy.
Authors
Ali K. Jaafar, Aurélie Paulo-Ramos, Guillaume Rastoldo, Bryan Veeren, Cynthia Planesse, Matthieu Bringart, Philippe Rondeau, Kévin Chemello, Olivier Meilhac, Gilles C. Lambert, Steeve Bourane
Abstract
Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM) is a rare neurodegenerative disease with largely elusive molecular mechanisms, impeding targeted therapeutic advancements. This study aimed to identify the critical molecule responsible for neuronal damage in HAM, its source, and the regulatory mechanisms controlling its expression. Utilizing patient-derived cells and established cell lines, we discovered that HTLV-1 Tax, in conjunction with Specificity Protein 1 (Sp1), enhanced the expression of repulsive guidance molecule A (RGMa), a molecule known to contribute to neuronal damage. RGMa expression was specifically upregulated in HTLV-1-infected cells from HAM patients, particularly in those expressing HTLV-1 Tax. Furthermore, in CD4+ cells from HAM patients, the level of H3K27me3 methylation upstream of the RGMA gene locus was reduced, making RGMA more prone to constitutive expression. We demonstrated that HTLV-1-infected cells in HAM inflict neuronal damage via RGMa. Crucially, the neutralizing antibody against RGMa, unasnemab/MT-3921, effectively mitigated this damage in a dose-responsive manner, highlighting RGMa's pivotal role in neuronal damage and its potential as a therapeutic target for alleviating neuronal damage in HAM.
Authors
Natsumi Araya, Makoto Yamagishi, Makoto Nakashima, Naomi Asahara, Kazuhiro Kiyohara, Satoko Aratani, Naoko Yagishita, Erika Horibe, Izumi Ishizaki, Toshiki Watanabe, Tomoo Sato, Kaoru Uchimaru, Yoshihisa Yamano
Abstract
The enzyme protein kinase C ε (PKCε) plays an important role in pain signaling and represents a promising therapeutic target for the treatment of chronic pain. We designed and generated a small molecule inhibitor of PKCε, CP612, and examined its effect in a rodent model of chemotherapy-induced neuropathic pain produced by paclitaxel, which does not respond well to current therapeutics. In addition, many patients with chronic pain use opiates, which over time can become ineffective, and attempts to discontinue them can increase pain thereby promoting sustained opioid use. Therefore, we also investigated if CP612 alters pain due to opioid withdrawal. We found that CP612 attenuated hyperalgesia produced by paclitaxel, and it both prevented and reversed hyperalgesia induced by opioid withdrawal. It was not self-administered and did not affect morphine self-administration. These findings suggest that inhibition of PKCε is an effective, nonaddictive strategy to treat chemotherapy-induced neuropathic pain, with the added benefit of preventing increases in pain that occur as opioid treatment is discontinued. This latter property could benefit individuals with chronic pain who find it difficult to discontinue opioids.
Authors
Adriana Gregory-Flores, Ivan J.M. Bonet, Stève Desaivre, Jon D. Levine, Stanton F. McHardy, Harmannus C. de Kraker, Nicholas A. Clanton, Peter M. LoCoco, Nicholas M. Russell, Caleb Fleischer, Robert O. Messing, Michela Marinelli
Abstract
The FDA-approved phosphodiesterase type 4 (PDE4) inhibitor, apremilast, has been recently investigated as a pharmacotherapy for alcohol use disorder (AUD) with promising efficacy in rodent models and humans. However, apremilast’s effects on mechanical allodynia associated with AUD as well as distinct responses of this drug between males and females are understudied. The present study examined the behavioral and electrophysiological effects of apremilast in Marchigian Sardinian alcohol-preferring (msP) rats and their Wistar counterparts. We used a 2–bottle choice (2-BC) alcohol drinking procedure and tested mechanical sensitivity across our drinking regimen. Spontaneous inhibitory GABA-mediated postsynaptic currents from the central nucleus of the amygdala (CeA) following apremilast application were tested in a subset of rats using ex vivo electrophysiology. Transcript levels for Pde4a or -4b subtypes were assessed for their modulation by alcohol. Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late abstinence. Apremilast increased GABAergic transmission in CeA slices of alcohol-exposed Wistars but not msP rats, suggesting neuroadaptations in msPs by excessive drinking and mechanical allodynia. Pde4 subtype transcript levels were increased in CeA by alcohol. These results suggest that apremilast alleviates co-occurring excessive drinking and pain sensitivity, and they further confirm PDE4’s role in pain-associated AUD.
Authors
Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M. St. Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R. Ozburn, Amanda J. Roberts, Roberto Ciccocioppo, Michal Bajo, Marisa Roberto
Abstract
Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light sensitive opsins into the surviving neurons of the inner retina. While up until now the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. Yet, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures moreover may serve to track treatment efficiency in clinical trials.
Authors
Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J. Gilhooley, Mark W. Hankins, Moritz Lindner
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