bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒09‒08
fifty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Unraveling the spatial organization and development of human thymocytes through integration of spatial transcriptomics and single-cell multi-omics profiling.
  2. Why are they leaving?
  3. Gut feelings regulate Treg cells.
  4. Trained immunity across organs.
  5. Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression.
  6. Spermidine controls autophagy during fasting.
  7. Older age reduces mtDNA mutation inheritance.
  8. A familiar drug can repair a broken heart.
  9. Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.
  10. The immune system of trans men reveals how hormones shape immunity.
  11. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
  12. Molecular architecture of the human brain vasculature.
  13. DNA hydroxymethylation in aging.
  14. Transparent mice made with light-absorbing dye reveal organs at work.
  15. Is it time to rethink the relationship between adipose inflammation and insulin resistance?
  16. Investigating the shared genetic architecture between depression and subcortical volumes.
  17. Emerging tumor repression of immune recognition is reversed by inhibiting DNA methylation.
  18. A phosphorylation-controlled switch confers cell cycle-dependent protein relocalization.
  19. scConfluence: single-cell diagonal integration with regularized Inverse Optimal Transport on weakly connected features.
  20. Engineered T cell therapy for central nervous system injury.
  21. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
  22. Japan moves to halt long-term postgraduate decline by tripling number of PhD graduates.
  23. Humans have evolved to digest starch more easily since the advent of farming.
  24. Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
  25. Found: a brain-wiring pattern linked to depression.
  26. Regulatory transposable elements in the encyclopedia of DNA elements.
  27. Immune system adaptation during gender-affirming testosterone treatment.
  28. Characteristics of blood-brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells.
  29. The brain heals the heart.
  30. How can I publish open access when I can't afford the fees?
  31. Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome.
  32. To conserve biodiversity, create spaces where natural selection is allowed free rein.
  33. Daily briefing: What causes obesity? Contentious topic gets an authoritative analysis.
  34. Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease.
  35. Detecting hidden brain injuries.
  36. scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood.
  37. Frontostriatal salience network expansion in individuals in depression.
  38. Distal activity patterns shape the spatial specificity of neurovascular coupling.
  39. CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection.
  40. Daily briefing: 'Mobesity' - how bigger vehicles are undermining the benefits of electric cars.
  41. Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease.
  42. Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
  43. Cell Painting Gallery: an open resource for image-based profiling.
  44. An artificial intelligence accelerated virtual screening platform for drug discovery.
  45. Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming.
  46. Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis.
  47. Imaging the epigenetic landscape in single cells to study aging trajectories.
  48. Public Health Crisis in Gaza-Reply.
  49. Holistic approach to carbon capture bridges the 'Valley of Death'.
  50. Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins.
  51. Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
  1. Nat Commun. 2024 Sep 06. 15(1): 7784
    Unraveling the spatial organization and development of human thymocytes through integration of spatial transcriptomics and single-cell multi-omics profiling.
    Yanchuan Li, Huamei Li, Cheng Peng, Ge Meng, Yijun Lu, Honglin Liu, Li Cui, Huan Zhou, Zhu Xu, Lingyun Sun, Lihong Liu, Qing Xiong, Beicheng Sun, Shiping Jiao.
      The structural components of the thymus are essential for guiding T cell development, but a thorough spatial view is still absent. Here we develop the TSO-his tool, designed to integrate multimodal data from single-cell and spatial transcriptomics to decipher the intricate structure of human thymus. Specifically, we characterize dynamic changes in cell types and critical markers, identifying ELOVL4 as a mediator of CD4+ T cell positive selection in the cortex. Utilizing the mapping function of TSO-his, we reconstruct thymic spatial architecture at single-cell resolution and recapitulates classical cell types and their essential co-localization for T cell development; additionally, previously unknown co-localization relationships such as that of CD8αα with memory B cells and monocytes are identified. Incorporating VDJ sequencing data, we also delineate distinct intermediate thymocyte states during αβ T cell development. Overall, these insights enhance our understanding of thymic biology and may inform therapeutic interventions targeting T cell-mediated immune responses.
    DOI:  https://doi.org/10.1038/s41467-024-51767-y
  2. Science. 2024 Sep 06. 385(6713): 1130
    Why are they leaving?
    David Caballero.
      
    DOI:  https://doi.org/10.1126/science.ads8200
  3. Nat Immunol. 2024 Sep;25(9): 1509
    Gut feelings regulate Treg cells.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01957-z
  4. Nat Immunol. 2024 Sep;25(9): 1509
    Trained immunity across organs.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-01958-y
  5. Nat Commun. 2024 Sep 03. 15(1): 7688
    Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression.
    Jean Lee, Leonid A Yurkovetskiy, Derek Reiman, Lara Frommer, Zoe Strong, Anthony Chang, George J Kahaly, Aly A Khan, Alexander V Chervonsky.
      Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51869-7
  6. Nat Aging. 2024 Sep 04.
    Spermidine controls autophagy during fasting.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00710-3
  7. Nat Aging. 2024 Sep 04.
    Older age reduces mtDNA mutation inheritance.
    Polyxeni Papadea, Nils-Göran Larsson.
      
    DOI:  https://doi.org/10.1038/s43587-024-00701-4
  8. Nature. 2024 Sep;633(8028): 11
    A familiar drug can repair a broken heart.
      
    Keywords:  Cardiovascular biology
    DOI:  https://doi.org/10.1038/d41586-024-02702-0
  9. Nat Commun. 2024 Aug 30. 15(1): 7557
    Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.
    Matteo Trovato, Daria Bunina, Umut Yildiz, Nadine Fernandez-Novel Marx, Michael Uckelmann, Vita Levina, Yekaterina Perez, Ana Janeva, Benjamin A Garcia, Chen Davidovich, Judith B Zaugg, Kyung-Min Noh.
      Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupts the deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal levels of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states at cis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.
    DOI:  https://doi.org/10.1038/s41467-024-51785-w
  10. Nature. 2024 Sep;633(8028): 38-40
    The immune system of trans men reveals how hormones shape immunity.
    Margaret M McCarthy.
      
    Keywords:  Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02432-3
  11. Nat Commun. 2024 Aug 29. 15(1): 7483
    Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
    Rongling Wang, Mario Gomez Salazar, Iris Pruñonosa Cervera, Amanda Coutts, Karen French, Marlene Magalhaes Pinto, Sabrina Gohlke, Ruben García-Martín, Matthias Blüher, Christopher J Schofield, Ioannis Kourtzelis, Roland H Stimson, Cécile Bénézech, Mark Christian, Tim J Schulz, Elias F Gudmundsson, Lori L Jennings, Vilmundur G Gudnason, Triantafyllos Chavakis, Nicholas M Morton, Valur Emilsson, Zoi Michailidou.
      Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-51718-7
  12. Nat Neurosci. 2024 Sep;27(9): 1638
    Molecular architecture of the human brain vasculature.
    Elisa Floriddia.
      
    DOI:  https://doi.org/10.1038/s41593-024-01759-4
  13. Nat Aging. 2024 Sep 04.
    DNA hydroxymethylation in aging.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s43587-024-00709-w
  14. Nature. 2024 Sep 05.
    Transparent mice made with light-absorbing dye reveal organs at work.
    Jude Coleman.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02887-4
  15. J Clin Invest. 2024 Sep 03. pii: e184663. [Epub ahead of print]134(17):
    Is it time to rethink the relationship between adipose inflammation and insulin resistance?
    Evan D Rosen, Shingo Kajimura.
      
    DOI:  https://doi.org/10.1172/JCI184663
  16. Nat Commun. 2024 Sep 02. 15(1): 7647
    Investigating the shared genetic architecture between depression and subcortical volumes.
    Mengge Liu, Lu Wang, Yujie Zhang, Haoyang Dong, Caihong Wang, Yayuan Chen, Qian Qian, Nannan Zhang, Shaoying Wang, Guoshu Zhao, Zhihui Zhang, Minghuan Lei, Sijia Wang, Qiyu Zhao, Feng Liu.
      Depression, a widespread and highly heritable mental health condition, profoundly affects millions of individuals worldwide. Neuroimaging studies have consistently revealed volumetric abnormalities in subcortical structures associated with depression. However, the genetic underpinnings shared between depression and subcortical volumes remain inadequately understood. Here, we investigate the extent of polygenic overlap using the bivariate causal mixture model (MiXeR), leveraging summary statistics from the largest genome-wide association studies for depression (N = 674,452) and 14 subcortical volumetric phenotypes (N = 33,224). Additionally, we identify shared genomic loci through conditional/conjunctional FDR analyses. MiXeR shows that subcortical volumetric traits share a substantial proportion of genetic variants with depression, with 44 distinct shared loci identified by subsequent conjunctional FDR analysis. These shared loci are predominantly located in intronic regions (58.7%) and non-coding RNA intronic regions (25.4%). The 269 protein-coding genes mapped by these shared loci exhibit specific developmental trajectories, with the expression level of 55 genes linked to both depression and subcortical volumes, and 30 genes linked to cognitive abilities and behavioral symptoms. These findings highlight a shared genetic architecture between depression and subcortical volumetric phenotypes, enriching our understanding of the neurobiological underpinnings of depression.
    DOI:  https://doi.org/10.1038/s41467-024-52121-y
  17. Nat Immunol. 2024 Sep 05.
    Emerging tumor repression of immune recognition is reversed by inhibiting DNA methylation.
      
    DOI:  https://doi.org/10.1038/s41590-024-01947-1
  18. Nat Cell Biol. 2024 Aug 29.
    A phosphorylation-controlled switch confers cell cycle-dependent protein relocalization.
    Xiaofu Cao, Shiying Huang, Mateusz M Wagner, Yuan-Ting Cho, Din-Chi Chiu, Krista M Wartchow, Artur Lazarian, Laura Beth McIntire, Marcus B Smolka, Jeremy M Baskin.
      Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP-GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods.
    DOI:  https://doi.org/10.1038/s41556-024-01495-8
  19. Nat Commun. 2024 Sep 05. 15(1): 7762
    scConfluence: single-cell diagonal integration with regularized Inverse Optimal Transport on weakly connected features.
    Jules Samaran, Gabriel Peyré, Laura Cantini.
      The abundance of unpaired multimodal single-cell data has motivated a growing body of research into the development of diagonal integration methods. However, the state-of-the-art suffers from the loss of biological information due to feature conversion and struggles with modality-specific populations. To overcome these crucial limitations, we here introduce scConfluence, a method for single-cell diagonal integration. scConfluence combines uncoupled autoencoders on the complete set of features with regularized Inverse Optimal Transport on weakly connected features. We extensively benchmark scConfluence in several single-cell integration scenarios proving that it outperforms the state-of-the-art. We then demonstrate the biological relevance of scConfluence in three applications. We predict spatial patterns for Scgn, Synpr and Olah in scRNA-smFISH integration. We improve the classification of B cells and Monocytes in highly heterogeneous scRNA-scATAC-CyTOF integration. Finally, we reveal the joint contribution of Fezf2 and apical dendrite morphology in Intra Telencephalic neurons, based on morphological images and scRNA.
    DOI:  https://doi.org/10.1038/s41467-024-51382-x
  20. Nature. 2024 Sep 04.
    Engineered T cell therapy for central nervous system injury.
    Wenqing Gao, Min Woo Kim, Taitea Dykstra, Siling Du, Pavle Boskovic, Cheryl F Lichti, Miguel A Ruiz-Cardozo, Xingxing Gu, Tal Weizman Shapira, Justin Rustenhoven, Camilo Molina, Igor Smirnov, Yifat Merbl, Wilson Z Ray, Jonathan Kipnis.
      Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide1, yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4+ T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries.
    DOI:  https://doi.org/10.1038/s41586-024-07906-y
  21. Nat Commun. 2024 Sep 01. 15(1): 7609
    Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
    F Nadalin, M J Marzi, M Pirra Piscazzi, P Fuentes-Bravo, S Procaccia, M Climent, P Bonetti, C Rubolino, B Giuliani, I Papatheodorou, J C Marioni, F Nicassio.
      Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-51424-4
  22. Nature. 2024 Aug 29.
    Japan moves to halt long-term postgraduate decline by tripling number of PhD graduates.
    Tim Hornyak.
      
    Keywords:  Funding; Government; Industry; Policy; Society
    DOI:  https://doi.org/10.1038/d41586-024-02718-6
  23. Nature. 2024 Sep 04.
    Humans have evolved to digest starch more easily since the advent of farming.
      
    Keywords:  Anthropology; Genomics
    DOI:  https://doi.org/10.1038/d41586-024-02825-4
  24. Nat Aging. 2024 Aug 29.
    Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
    Suchira Gallage, Elaine E Irvine, Jose Efren Barragan Avila, Virinder Reen, Silvia M A Pedroni, Imanol Duran, Vikas Ranvir, Sanjay Khadayate, Joaquim Pombo, Sharon Brookes, Danijela Heide, Gopuraja Dharmalingham, Agharul I Choudhury, Indrabahadur Singh, Nicolás Herranz, Santiago Vernia, Mathias Heikenwalder, Jesús Gil, Dominic J Withers.
      Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00695-z
  25. Nature. 2024 Sep 04.
    Found: a brain-wiring pattern linked to depression.
    Sara Reardon.
      
    Keywords:  Brain; Depression; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02857-w
  26. Nat Commun. 2024 Aug 31. 15(1): 7594
    Regulatory transposable elements in the encyclopedia of DNA elements.
    Alan Y Du, Jason D Chobirko, Xiaoyu Zhuo, Cédric Feschotte, Ting Wang.
      Transposable elements (TEs) comprise ~50% of our genome, but knowledge of how TEs affect genome evolution remains incomplete. Leveraging ENCODE4 data, we provide the most comprehensive study to date of TE contributions to the regulatory genome. We find 236,181 (~25%) human candidate cis-regulatory elements (cCREs) are TE-derived, with over 90% lineage-specific since the human-mouse split, accounting for 8-36% of lineage-specific cCREs. Except for SINEs, cCRE-associated transcription factor (TF) motifs in TEs are derived from ancestral TE sequence more than expected by chance. We show that TEs may adopt similar regulatory activities of elements near their integration site. Since human-mouse divergence, TEs have contributed 3-56% of TF binding site turnover events across 30 examined TFs. Finally, TE-derived cCREs are similar to non-TE cCREs in terms of MPRA activity and GWAS variant enrichment. Overall, our results substantiate the notion that TEs have played an important role in shaping the human regulatory genome.
    DOI:  https://doi.org/10.1038/s41467-024-51921-6
  27. Nature. 2024 Sep;633(8028): 155-164
    Immune system adaptation during gender-affirming testosterone treatment.
    Tadepally Lakshmikanth, Camila Consiglio, Fabian Sardh, Rikard Forlin, Jun Wang, Ziyang Tan, Hugo Barcenilla, Lucie Rodriguez, Jamie Sugrue, Peri Noori, Margarita Ivanchenko, Laura Piñero Páez, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Henrik Ryberg, Åsa Hallgren, Christian Pou, Yang Chen, Jaromír Mikeš, Anna James, Per Dahlqvist, Jeanette Wahlberg, Anders Hagelin, Mats Holmberg, Marie Degerblad, Magnus Isaksson, Darragh Duffy, Olle Kämpe, Nils Landegren, Petter Brodin.
      Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.
    DOI:  https://doi.org/10.1038/s41586-024-07789-z
  28. Nat Neurosci. 2024 Aug 29.
    Characteristics of blood-brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells.
    Sarah J Pfau, Urs H Langen, Theodore M Fisher, Indumathi Prakash, Faheem Nagpurwala, Ricardo A Lozoya, Wei-Chung Allen Lee, Zhuhao Wu, Chenghua Gu.
      The blood-brain barrier (BBB) protects the brain and maintains neuronal homeostasis. BBB properties can vary between brain regions to support regional functions, yet how BBB heterogeneity occurs is poorly understood. Here, we used single-cell and spatial transcriptomics to compare the mouse median eminence, one of the circumventricular organs that has naturally leaky blood vessels, with the cortex. We identified hundreds of molecular differences in endothelial cells (ECs) and perivascular cells, including astrocytes, pericytes and fibroblasts. Using electron microscopy and an aqueous-based tissue-clearing method, we revealed distinct anatomical specializations and interaction patterns of ECs and perivascular cells in these regions. Finally, we identified candidate regionally enriched EC-perivascular cell ligand-receptor pairs. Our results indicate that both molecular specializations in ECs and unique EC-perivascular cell interactions contribute to BBB functional heterogeneity. This platform can be used to investigate BBB heterogeneity in other regions and may facilitate the development of central nervous system region-specific therapeutics.
    DOI:  https://doi.org/10.1038/s41593-024-01743-y
  29. Nat Neurosci. 2024 Sep;27(9): 1638
    The brain heals the heart.
    Leonie Welberg.
      
    DOI:  https://doi.org/10.1038/s41593-024-01761-w
  30. Nature. 2024 Sep 02.
    How can I publish open access when I can't afford the fees?
    Nikki Forrester.
      
    Keywords:  Lab life; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-02849-w
  31. Nat Commun. 2024 Sep 03. 15(1): 7681
    Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome.
    Marius Klein, Klemens Wild, Irmgard Sinning.
      Nascent chains undergo co-translational enzymatic processing as soon as their N-terminus becomes accessible at the ribosomal polypeptide tunnel exit (PTE). In eukaryotes, N-terminal methionine excision (NME) by Methionine Aminopeptidases (MAP1 and MAP2), and N-terminal acetylation (NTA) by N-Acetyl-Transferase A (NatA), is the most common combination of subsequent modifications carried out on the 80S ribosome. How these enzymatic processes are coordinated in the context of a rapidly translating ribosome has remained elusive. Here, we report two cryo-EM structures of multi-enzyme complexes assembled on vacant human 80S ribosomes, indicating two routes for NME-NTA. Both assemblies form on the 80S independent of nascent chain substrates. Irrespective of the route, NatA occupies a non-intrusive 'distal' binding site on the ribosome which does not interfere with MAP1 or MAP2 binding nor with most other ribosome-associated factors (RAFs). NatA can partake in a coordinated, dynamic assembly with MAP1 through the hydra-like chaperoning function of the abundant Nascent Polypeptide-Associated Complex (NAC). In contrast to MAP1, MAP2 completely covers the PTE and is thus incompatible with NAC and MAP1 recruitment. Together, our data provide the structural framework for the coordinated orchestration of NME and NTA in protein biogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-51964-9
  32. Nature. 2024 Sep;633(8028): 36
    To conserve biodiversity, create spaces where natural selection is allowed free rein.
    Bruno Fady, Magda Bou Dagher Kharrat.
      
    Keywords:  Ecology; Environmental sciences; Policy
    DOI:  https://doi.org/10.1038/d41586-024-02854-z
  33. Nature. 2024 Sep 02.
    Daily briefing: What causes obesity? Contentious topic gets an authoritative analysis.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02867-8
  34. Nat Cardiovasc Res. 2024 Jun;3(6): 754-769
    Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease.
    Jacob Bergstedt, Joëlle A Pasman, Ziyan Ma, Arvid Harder, Shuyang Yao, Nadine Parker, Jorien L Treur, Dirk J A Smit, Oleksandr Frei, Alexey A Shadrin, Joeri J Meijsen, Qing Shen, Sara Hägg, Per Tornvall, Alfonso Buil, Thomas Werge, Jens Hjerling-Leffler, Thomas D Als, Anders D Børglum, Cathryn M Lewis, Andrew M McIntosh, Unnur A Valdimarsdóttir, Ole A Andreassen, Patrick F Sullivan, Yi Lu, Fang Fang.
      Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD-atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD-CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.
    DOI:  https://doi.org/10.1038/s44161-024-00488-y
  35. Nature. 2024 Aug 29.
    Detecting hidden brain injuries.
    Amanda B Keener.
      
    Keywords:  Brain; Imaging; Neuroscience; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-024-02788-6
  36. Nat Commun. 2024 Aug 31. 15(1): 7567
    scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood.
    Marc Jan Bonder, Stephen J Clark, Felix Krueger, Siyuan Luo, João Agostinho de Sousa, Aida M Hashtroud, Thomas M Stubbs, Anne-Katrien Stark, Steffen Rulands, Oliver Stegle, Wolf Reik, Ferdinand von Meyenn.
      Ageing is the accumulation of changes and decline of function of organisms over time. The concept and biomarkers of biological age have been established, notably DNA methylation-based clocks. The emergence of single-cell DNA methylation profiling methods opens the possibility of studying the biological age of individual cells. Here, we generate a large single-cell DNA methylation and transcriptome dataset from mouse peripheral blood samples, spanning a broad range of ages. The number of genes expressed increases with age, but gene-specific changes are small. We next develop scEpiAge, a single-cell DNA methylation age predictor, which can accurately predict age in (very sparse) publicly available datasets, and also in single cells. DNA methylation age distribution is wider than technically expected, indicating epigenetic age heterogeneity and functional differences. Our work provides a foundation for single-cell and sparse data epigenetic age predictors, validates their functionality and highlights epigenetic heterogeneity during ageing.
    DOI:  https://doi.org/10.1038/s41467-024-51833-5
  37. Nature. 2024 Sep 04.
    Frontostriatal salience network expansion in individuals in depression.
    Charles J Lynch, Immanuel G Elbau, Tommy Ng, Aliza Ayaz, Shasha Zhu, Danielle Wolk, Nicola Manfredi, Megan Johnson, Megan Chang, Jolin Chou, Indira Summerville, Claire Ho, Maximilian Lueckel, Hussain Bukhari, Derrick Buchanan, Lindsay W Victoria, Nili Solomonov, Eric Goldwaser, Stefano Moia, Cesar Caballero-Gaudes, Jonathan Downar, Fidel Vila-Rodriguez, Zafiris J Daskalakis, Daniel M Blumberger, Kendrick Kay, Amy Aloysi, Evan M Gordon, Mahendra T Bhati, Nolan Williams, Jonathan D Power, Benjamin Zebley, Logan Grosenick, Faith M Gunning, Conor Liston.
      Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2-4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.
    DOI:  https://doi.org/10.1038/s41586-024-07805-2
  38. Nat Neurosci. 2024 Sep 04.
    Distal activity patterns shape the spatial specificity of neurovascular coupling.
    Éric Martineau, Antoine Malescot, Nouha Elmkinssi, Ravi L Rungta.
      Neurovascular coupling links brain activity to local changes in blood flow, forming the basis for non-invasive brain mapping. Using multiscale imaging, we investigated how vascular activity spatially relates to neuronal activity elicited by single whiskers across different columns and layers of mouse cortex. Here we show that mesoscopic hemodynamic signals quantitatively reflect neuronal activity across space but are composed of a highly heterogeneous pattern of responses across individual vessel segments that is poorly predicted by local neuronal activity. Rather, this heterogeneity is dependent on vessel directionality, specifically in thalamocortical input layer 4, where capillaries respond preferentially to neuronal activity patterns along their downstream perfusion domain. Thus, capillaries fine-tune blood flow based on distant activity and encode laminar-specific activity patterns. These findings imply that vascular anatomy sets a resolution limit on functional imaging signals, where individual blood vessels inaccurately report neuronal activity in their immediate vicinity but, instead, integrate activity patterns along the vascular arbor.
    DOI:  https://doi.org/10.1038/s41593-024-01756-7
  39. Immunity. 2024 Aug 27. pii: S1074-7613(24)00375-3. [Epub ahead of print]
    CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection.
    Joshua D Bromley, Sharie Keanne C Ganchua, Sarah K Nyquist, Pauline Maiello, Michael Chao, H Jacob Borish, Mark Rodgers, Jaime Tomko, Kara Kracinovsky, Douaa Mugahid, Son Nguyen, Qianchang Dennis Wang, Jacob M Rosenberg, Edwin C Klein, Hannah P Gideon, Roisin Floyd-O'Sullivan, Bonnie Berger, Charles A Scanga, Philana Ling Lin, Sarah M Fortune, Alex K Shalek, JoAnne L Flynn.
      Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4+ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4+ T cell-depleted granulomas, we found that the presence of CD4+ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8+ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.
    Keywords:  CD4 T cells; CD4 depletion; CD8 T cells; Mycobacterium tuberculosis; concomitant immunity; granuloma; macaque; non-human primate; reinfection; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.002
  40. Nature. 2024 Aug 30.
    Daily briefing: 'Mobesity' - how bigger vehicles are undermining the benefits of electric cars.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02861-0
  41. Nat Cardiovasc Res. 2024 Jun;3(6): 714-733
    Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease.
    Jordi Lambert, Sebnem Oc, Matthew D Worssam, Daniel Häußler, Charles U Solomon, Nichola L Figg, Ruby Baxter, Maria Imaz, James C K Taylor, Kirsty Foote, Alison Finigan, Krishnaa T Mahbubani, Tom R Webb, Shu Ye, Martin R Bennett, Achim Krüger, Mikhail Spivakov, Helle F Jørgensen.
      Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1-CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.
    DOI:  https://doi.org/10.1038/s44161-024-00474-4
  42. Cell Metab. 2024 Sep 03. pii: S1550-4131(24)00330-9. [Epub ahead of print]36(9): 1911-1913
    Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
    Hee-Hoon Kim, Vishwa Deep Dixit.
      Organismal aging involves several hallmark pathways, including chronic inflammation and metabolic dysfunction. However, the origin of age-related inflammation is incompletely understood. In a recent study published in Nature,1 Widjaja et al. show that blocking the age-related increase in IL-11 restores immune-metabolic homeostasis and extends healthspan and lifespan in mice.
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.003
  43. Nat Methods. 2024 Sep 02.
    Cell Painting Gallery: an open resource for image-based profiling.
    Erin Weisbart, Ankur Kumar, John Arevalo, Anne E Carpenter, Beth A Cimini, Shantanu Singh.
      
    DOI:  https://doi.org/10.1038/s41592-024-02399-z
  44. Nat Commun. 2024 Sep 05. 15(1): 7761
    An artificial intelligence accelerated virtual screening platform for drug discovery.
    Guangfeng Zhou, Domnita-Valeria Rusnac, Hahnbeom Park, Daniele Canzani, Hai Minh Nguyen, Lance Stewart, Matthew F Bush, Phuong Tran Nguyen, Heike Wulff, Vladimir Yarov-Yarovoy, Ning Zheng, Frank DiMaio.
      Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel NaV1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to NaV1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery.
    DOI:  https://doi.org/10.1038/s41467-024-52061-7
  45. Nature. 2024 Sep 04.
    Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming.
    Jean-Rémi Lavillegrand, Rida Al-Rifai, Sara Thietart, Théo Guyon, Marie Vandestienne, Raphael Cohen, Vincent Duval, Xiaodan Zhong, Daniel Yen, Mumin Ozturk, Yutaka Negishi, Joanne Konkel, Emmanuel Pinteaux, Olivia Lenoir, Jose Vilar, Ludivine Laurans, Bruno Esposito, Marius Bredon, Harry Sokol, Marc Diedisheim, Antoine-Emmanuel Saliba, Alma Zernecke, Clément Cochain, Jessica Haub, Alain Tedgui, Nancy A Speck, Soraya Taleb, Musa M Mhlanga, Andreas Schlitzer, Niels P Riksen, Hafid Ait-Oufella.
      Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications1. However, individuals often change their dietary habits over time2, and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe-/-Rag2-/- mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX13, promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1β, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1β pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1β-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD.
    DOI:  https://doi.org/10.1038/s41586-024-07693-6
  46. Nat Cardiovasc Res. 2024 Sep 04.
    Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis.
    Divyesh Joshi, Brian G Coon, Raja Chakraborty, Hanqiang Deng, Ziyu Yang, Muhammad Usman Babar, Pablo Fernandez-Tussy, Emily Meredith, John Attanasio, Nikhil Joshi, James G Traylor, Anthony Wayne Orr, Carlos Fernandez-Hernando, Stephania Libreros, Martin A Schwartz.
      Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD.
    DOI:  https://doi.org/10.1038/s44161-024-00522-z
  47. Nat Aging. 2024 Aug 29.
    Imaging the epigenetic landscape in single cells to study aging trajectories.
      
    DOI:  https://doi.org/10.1038/s43587-024-00689-x
  48. JAMA. 2024 Sep 06.
    Public Health Crisis in Gaza-Reply.
    Anand R Habib, Nadir Ijaz.
      
    DOI:  https://doi.org/10.1001/jama.2024.16666
  49. Nature. 2024 Sep 03.
    Holistic approach to carbon capture bridges the 'Valley of Death'.
      
    Keywords:  Computer science; Engineering; Materials science
    DOI:  https://doi.org/10.1038/d41586-024-02819-2
  50. Nat Commun. 2024 Sep 04. 15(1): 7719
    Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins.
    Tom J Arrowsmith, Xibing Xu, Shangze Xu, Ben Usher, Peter Stokes, Megan Guest, Agnieszka K Bronowska, Pierre Genevaux, Tim R Blower.
      Nucleotidyltransferases (NTases) control diverse physiological processes, including RNA modification, DNA replication and repair, and antibiotic resistance. The Mycobacterium tuberculosis NTase toxin family, MenT, modifies tRNAs to block translation. MenT toxin activity can be stringently regulated by diverse MenA antitoxins. There has been no unifying mechanism linking antitoxicity across MenT homologues. Here we demonstrate through structural, biochemical, biophysical and computational studies that despite lacking kinase motifs, antitoxin MenA1 induces auto-phosphorylation of MenT1 by repositioning the MenT1 phosphoacceptor T39 active site residue towards bound nucleotide. Finally, we expand this predictive model to explain how unrelated antitoxin MenA3 is similarly able to induce auto-phosphorylation of cognate toxin MenT3. Our study reveals a conserved mechanism for the control of tuberculosis toxins, and demonstrates how active site auto-phosphorylation can regulate the activity of widespread NTases.
    DOI:  https://doi.org/10.1038/s41467-024-51934-1
  51. Nat Commun. 2024 Sep 04. 15(1): 7730
    Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models.
    Emma Puighermanal, Marta Luna-Sánchez, Alejandro Gella, Gunter van der Walt, Andrea Urpi, María Royo, Paula Tena-Morraja, Isabella Appiah, Maria Helena de Donato, Fabien Menardy, Patrizia Bianchi, Anna Esteve-Codina, Laura Rodríguez-Pascau, Cristina Vergara, Mercè Gómez-Pallarès, Giovanni Marsicano, Luigi Bellocchio, Marc Martinell, Elisenda Sanz, Sandra Jurado, Francesc Xavier Soriano, Pilar Pizcueta, Albert Quintana.
      Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.
    DOI:  https://doi.org/10.1038/s41467-024-51884-8
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