Research News

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.

Guarnieri JW, Lie T, Albrecht YES, Hewin P, Jurado KA, Widjaja GA, Zhu Y, McManus MJ, Kilbaugh TJ, Keith K, Potluri P, Taylor D, Angelin A, Murdock DG, Wallace DC. Mitochondrial antioxidants abate SARS-COV-2 pathology in mice. Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2321972121. doi: 10.1073/pnas.2321972121. Epub 2024 Jul 15. PMID: 39008677.

https://pubmed.ncbi.nlm.nih.gov/39008677/

Summary: “Osteoarthritis (OA) is a degenerative joint disease and the most common form of arthritis globally, which is a leading cause of disability among the elderly population. The typical symptoms of OA include pain and stiffness in the affected joints. The current treatment strategies for OA include regular exercise, acupuncture, and massage. Patients with severe OA have to undergo surgery, such as joint replacement. Although the etiology of OA remains not fully understood, it is well recognized that the pathogenesis and progression of OA are closely associated with abnormal immune responses in the cartilage microenvironment (1). Apart from regulatory proteins, emerging evidence has underscored the crucial roles of immunoregulatory metabolites in various immune disorders (2). Compared to traditional medications, natural metabolites, many of which are derived from our daily diet, usually have advantages in terms of higher availability, proven safety, and lower costs. Therefore, the diet-based intervention of immunological diseases has been attracting increasingly more attention in recent years. However, the metabolic alterations in the cartilage microenvironment of OA patients and their potential effects on OA pathogenesis remain largely unexplored to date. Herein, we report a unique, anti-OA role of vitamin B1 (VB1), and the underlying mechanism was further explored.”

Shen S, Liang Y, Zhao Y, Hu Z, Huang Y, Wu Y, Liu Y, Fan S, Wang Q, Xiao P. Dietary supplementation of vitamin B1 prevents the pathogenesis of osteoarthritis. Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2408160121. doi: 10.1073/pnas.2408160121. Epub 2024 Jul 18. PMID: 39024114.

https://www.pnas.org/doi/10.1073/pnas.2408160121

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Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, Rothammer N, Tsvilovskyy V, Lorenz SM, Raich L, Bal LC, Vieira V, Wagner I, Bauer S, Glatzel M, Conrad M, Merkler D, Freichel M, Friese MA. STING orchestrates the neuronal inflammatory stress response in multiple sclerosis. Cell. 2024 Jun 7:S0092-8674(24)00576-2. doi: 10.1016/j.cell.2024.05.031. Epub ahead of print. PMID: 38878778.

https://www.cell.com/cell/fulltext/S0092-8674(24)00576-2

Abstract:    Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Jiang Y, Luo C, Wang J, Palaniyappan L, Chang X, Xiang S, Zhang J, Duan M, Huang H, Gaser C, Nemoto K, Miura K, Hashimoto R, Westlye LT, Richard G, Fernandez-Cabello S, Parker N, Andreassen OA, Kircher T, Nenadić I, Stein F, Thomas-Odenthal F, Teutenberg L, Usemann P, Dannlowski U, Hahn T, Grotegerd D, Meinert S, Lencer R, Tang Y, Zhang T, Li C, Yue W, Zhang Y, Yu X, Zhou E, Lin CP, Tsai SJ, Rodrigue AL, Glahn D, Pearlson G, Blangero J, Karuk A, Pomarol-Clotet E, Salvador R, Fuentes-Claramonte P, Garcia-León MÁ, Spalletta G, Piras F, Vecchio D, Banaj N, Cheng J, Liu Z, Yang J, Gonul AS, Uslu O, Burhanoglu BB, Uyar Demir A, Rootes-Murdy K, Calhoun VD, Sim K, Green M, Quidé Y, Chung YC, Kim WS, Sponheim SR, Demro C, Ramsay IS, Iasevoli F, de Bartolomeis A, Barone A, Ciccarelli M, Brunetti A, Cocozza S, Pontillo G, Tranfa M, Park MTM, Kirschner M, Georgiadis F, Kaiser S, Van Rheenen TE, Rossell SL, Hughes M, Woods W, Carruthers SP, Sumner P, Ringin E, Spaniel F, Skoch A, Tomecek D, Homan P, Homan S, Omlor W, Cecere G, Nguyen DD, Preda A, Thomopoulos SI, Jahanshad N, Cui LB, Yao D, Thompson PM, Turner JA, van Erp TGM, Cheng W; ENIGMA Schizophrenia Consortium; Feng J; ZIB Consortium. Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm. Nat Commun. 2024 Jul 17;15(1):5996. doi: 10.1038/s41467-024-50267-3. PMID: 39013848; PMCID: PMC11252381.

https://pubmed.ncbi.nlm.nih.gov/39013848/

Sun, Y. et al: In Vivo editing of lung STEM cells for durable gene correction in mice. Science https://doi.org/10.1126/science. adk9428 (2024).

https://www.science.org/doi/10.1126/science.adk9428

Abstract:

Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials.

Woo, M.S., Engler, J.B. & Friese, M.A. The neuropathobiology of multiple sclerosis. Nat. Rev. Neurosci. 25: 493–513 (2024). https://doi.org/10.1038/s41583-024-00823-z

https://www.nature.com/articles/s41583-024-00823-z

Abstract: “MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.”

Dolcetti E, Musella A, Balletta S, Gilio L, Bruno A, Stampanoni Bassi M, Lauritano G, Buttari F, Fresegna D, Tartacca A, Mariani F, Palmerio F, Rovella V, Ferese R, Gambardella S, Giardina E, Finardi A, Furlan R, Mandolesi G, Centonze D, De Vito F. Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity. Int J Mol Sci. 2024 May 11;25(10):5253. doi: 10.3390/ijms25105253. PMID: 38791290; PMCID: PMC11121620.

https://pubmed.ncbi.nlm.nih.gov/38791290/

Abstract:  “Multiple sclerosis (MS) is a condition characterized by inflammation in the central nervous system (CNS), impacting sensory, motor, and cognitive abilities. Globally, around three million individuals are affected by MS, with up to 97,000 cases in Iran attributed to genetic predispositions along with various environmental factors like smoking. Cognitive impairment affects a significant portion of patients, ranging from 45% to 70%. This study investigates the impact of regular aerobic swimming exercise for four weeks, mild cognitive impairment induced by encephalomyelitis, and their combination on the expression of microRNA-142-3p and its correlation with the release of brain-derived neurotrophic factor (BDNF) in relation to spatial memory. Twenty-one C57BL/6 mice were divided into three groups. RT-PCR was used for microRNA expression analysis, and BDNF levels were assessed via western blotting. Clinical scores and animal weights were monitored daily. EAE induction led to an increase in microRNA-142-3p expression and a decrease in BDNF levels compared to the control group. Exercise inversed them significantly, and improved spatial memory. Our findings indicate that engaging in regular swimming exercise can counteract the up-regulation of miR-142-3p in brain tissue, which likely contributes to mild cognitive impairment induced by MS. Additionally, the increase in BDNF following exercise appears to be associated with miR-142-3p and the enhancement of cognitive function. Thus, the therapeutic benefits of exercise, particularly in releasing BDNF to improve cognitive function in MS patients, warrant consideration. Lifestyle modifications have the potential to effectively modulate environmental influences and ethnicity, underscoring their significance in MS management.”

Banasadegh S, Shahrbanian S, Gharakhanlou R, Kordi MR, Mohammad Soltani B. Enhancing brain health: Swimming-induced BDNF release and epigenetic influence in MS female mouse models. J Ethn Subst Abuse. 2024 Jun 20:1-17. doi: 10.1080/15332640.2024.2365230. Epub ahead of print. PMID: 38900673.

https://pubmed.ncbi.nlm.nih.gov/38900673/

Editor’s summary: “Vitamin B12 deficiency can lead to neurological deficits, sometimes in the absence of anemia, and mice and patients with mutations in the transcobalamin receptor CD320 do not develop anemia, suggesting that the mechanisms governing B12 uptake in different tissues are not fully understood. Here, Pluvinage and colleagues identified an autoantibody against CD320 in a patient with progressive neurological symptoms that blocked B12 uptake in endothelial cells and was associated with central but not peripheral vitamin B12 deficiency. The authors identified additional individuals with anti-CD320 autoantibodies and also found an association with neuropsychiatric systemic lupus erythematosus. The low-density lipoprotein receptor was identified as a noncanonical transcobalamin receptor in the periphery only, potentially explaining why anti-CD320 autoantibodies lead to central but not peripheral vitamin B12 deficiency. ”

Pluvinage JV et al. : Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Science  Translational Medicine 16. (753): DOI: 10.1126/scitranslmed.adl3758 , June 26, 2024.

https://www.science.org/doi/10.1126/scitranslmed.adl3758