Howard Hughes Medical Institute (HHMI)’s Post

𝗖𝗼𝗺𝗽𝗿𝗲𝗵𝗲𝗻𝘀𝗶𝘃𝗲 𝗿𝗲𝘃𝗶𝗲𝘄 𝗼𝗳 𝗶𝗺𝗽𝗼𝗿𝘁𝗮𝗻𝘁 𝗰𝗲𝗹𝗹 𝗱𝗲𝗮𝘁𝗵 𝗺𝗲𝗰𝗵𝗮𝗻𝗶𝘀𝗺: #𝗙𝗲𝗿𝗿𝗼𝗽𝘁𝗼𝘀𝗶𝘀: An international team comprising 90 authors presents the status of research on “ferroptosis”, a cell death mechanism caused by excess iron and oxygen radicals. Ferroptosis plays an important role in many types of cancer, neurological diseases, stroke, heart attack and other medically relevant situations. Four researchers from Heinrich Heine University Düsseldorf (HHU)/University Hospital Düsseldorf (UKD) have made key contributions to the comprehensive review of this cell death mechanism recently published in the scientific journal Redox Biology. Ferroptosis is a cell death mechanism that has only become known comparatively recently, being named in 2012. This so-called non-apoptotic cell death occurs when too many oxygen radicals and free iron are present in a cell. Certain molecules in the cell membrane, namely phospholipids, are then oxidised and thereby damaged. Without a corresponding counter-reaction, the cell membrane is eventually destroyed, leading to the death of the cell as a whole. 𝗥𝗲𝗮𝗱 𝗺𝗼𝗿𝗲: https://lnkd.in/e5As48it Heinrich-Heine-Universität Düsseldorf (HHU), Marcus Conrad, Carsten Bernd, Hamed Alborzinia, Vera Skafar Amen, Scott Ayton, Uladzimir Barayeu, Alexander Bartelt, Hülya Bayir, Christina Bebber, Kivanç Birsoy, Jan Böttcher, Simone Brabletz, Thomas Brabletz, Ashley R. Brown, Bernhard Brüne, Giorgia Bulli

How GPCR couple to multiple G-proteins GPCRs are the largest receptor class, affecting almost every aspect of human physiology, with 35% of all approved drugs acting on GPCRs. They regulate sensory and neuronal signaling, as well as a myriad of processes associated with cell homeostasis, growth, and immune response. In a groundbreaking study, a multinational research team has carried out experimental and computational studies to elucidate the mechanisms behind G protein selectivity and efficacy in the human adenosine A2A receptor (A2AR). A2AR is a member of major drug targets G protein-coupled receptor (GPCR) superfamily, which engages the G protein and initiates cell signaling, influencing heart health, inflammation, cancer, and brain diseases. Scientists have made a breakthrough in understanding how A2AR can engage and activate multiple binding G-proteins and the mechanisms of this selective coupling. The research team discovered that the hallmark coupling promiscuity in A2AR is a direct consequence of changes in activation conformations. Moreover, the long-range (allosteric) communication mechanisms elegantly control the sampling of specific conformers within a dynamic conformational ensemble. This study offers profound insights into GPCRs selectivity and biased signaling. #ScienceMission #sciencenewshighlights https://lnkd.in/g35FUEtJ

#neurodegenerativedisease #microglia #monocyte Patient-specific monocyte-derived microglia as a screening tool for neurodegenerative diseases https://lnkd.in/dBW2RrQH Hazel Quek The University of Queensland QIMR Berghofer Medical Research Institute Microglia, the main driver of neuroinflammation, play a central role in the initiation and exacerbation of various neurodegenerative diseases and are now considered a promising therapeutic target. Previous studies on in vitro human microglia and in vivo rodent models lacked scalability, consistency, or physiological relevance, which deterred successful therapeutic outcomes for the past decade. Here we review human blood monocyte-derived microglia-like cells as a robust and consistent approach to generate a patient-specific microglia-like model that can be used in extensive cohort studies for drug testing. We will highlight the strength and applicability of human blood monocyte-derived microglia-like cells to increase translational outcomes by reviewing the advantages of human blood monocyte-derived microglia-like cells in addressing patient heterogeneity and stratification, the basis of personalized medicine.

Potential novel therapeutics for Niemann-Pick C disease The NAD-autophagy pathway is gaining attention in the field of aging. NAD is a co-factor involved in metabolic responses, including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation, which, in turn, regulate autophagy and immunity. Here, researchers studied this pathway in Niemann-Pick C (NPC) disease, a rare storage disorder of cholesterol and other lipids that shares histopathological features with Alzheimer’s disease. NPC1 cells presented mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of NAD pools and apoptosis. A NAD precursor restored NAD levels and improved the viability of NPC1 patient-derived cortical neurons. In parallel, they identified celecoxib and memantine as autophagy activators, which restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Notable, in the past we showed that memantine, an FDA-approved drug, delayed the apparition of neurological signs in mouse models of neuropathic Gaucher disease https://lnkd.in/em5RC4u9. These results highlight novel therapeutics for NPC disease and potentially for Alzheimer’s´ and other neurodegenerative diseases. https://lnkd.in/eUb8yWSw #genetics #genmomics #precisionmedicine #genomicmedicine #raredisease #niemannpick #gaucher #alzheimer #therapeutics #metabolism #aging #longevity #omics #metabolomics #brain #neurology #neurodegeneration #neuroscience #immunology #immunity #autophagy #pathology #drugrepurposing #drugdevelopment #biotechnology #innovation #research #science #sciencecommunication 

Tunneling nanotubes (TNTs) have been demonstrated to facilitate the rapid exchange of organelles, vesicles, and proteins between cells. These structures have been identified in the CNS and form between neurons as well as neurons and glia. Interest has grown in these structures as conduits for the transportation and spread of pathological aggregating proteins such as alpha-synuclein (α-syn) and tau. In these two publications, TNTs were demonstrated using both mouse and human cells to facilitate the transfer of α-Syn aggregates predominantly from neuronal to microglial cells, and that microglia transfer mitochondria preferably to α-Syn burdened neuronal cells over the healthy ones. As a result of the neuron-microglia contacts with TNTs, microglia can extract toxic proteins (α-syn and tau) and alleviate cytotoxic protein accumulation. The molecular mechanisms of TNT intercellular transfer of α-syn were found to be dependent on P2Y12R-Rac-PAK-F-actin signaling pathway (a potential drug target for increasing efficiency). The reverse transfer within TNTs of intact and functional mitochondria from microglia to neurons significantly reduced oxidative stress and enhanced neuronal health without detriment to microglia themselves. The impact of genetic variants associated with increased risk of synucleinopathies (PD) or primary (FTD) and secondary (AD) tauopathies were demonstrated to impair microglial support of neurons by reducing TNT-mediated aggregate removal. These data highlight timely and efficient aggregate clearance mechanisms as well as microglia support as important mechanisms of neuroprotection. Chakraborty, R., Nonaka, T., Hasegawa, M. et al. Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria. Cell Death Dis 14, 329 (2023). https://lnkd.in/ghSWKTy8 Scheiblich H, Eikens F, Wischhof L, Opitz S, Jüngling K, Cserép C, Schmidt SV, Lambertz J, Bellande T, Pósfai B, Geck C. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron. 2024 Jul 25.

Latest discovery! The scientists published their latest discovery titled “PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome” On Cell. They found the immunogenicity of PNMA2 could result in neurological deficits.   The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. The scientists show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external “spike” PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits. The article DOI: 10.1016/j.cell.2024.01.009 In addition, we provide a number of genetically engineered PNMA2-targeted mouse models, some of which are ready to be shipped in as early as two weeks. Contact us at service.us@modelorg.com to learn more.  #mousemodel #neuroscienceresearch #neurologicaldisorders #SMOC

In the past few decades, the surging incidence of metabolic disorders, particularly obesity and overweight conditions, has become a prominent issue in public health. An intriguing hypothesis emerges when considering transgenerational inheritance—the idea that genetic and epigenetic imprints linked to obesity might exert a significant impact on the onset of Prostate Cancer. This paper delves into the intricate mechanisms by which obesity disrupts prostate homeostasis, acting as a catalyst for the initiation of prostate cancer. Additionally, we explore the fascinating interplay between the transgenerational transmission of obesity-related traits and the predisposition to prostate cancer.

📍 Energy-Producing Enzyme Fuels the Brain with Promise for Treating Parkinson’s Disease In Parkinson’s disease, neurons in parts of the brain gradually weaken and die, leading people to experience worsening problems with movement and other symptoms. While the causes of this disease aren’t fully known, studies have suggested the Parkinson’s brain lacks fuel to power dopamine-producing neurons that are essential for movement. When too many of those neurons are lost, Parkinson’s disease symptoms appear. But what if there was a way to boost energy levels in the brain and stop the neurodegenerative process in its tracks? While the findings are preliminary, an #NIH-supported study reported in Science Advances takes an encouraging step toward this goal. The key element, according to the new work, is an energy-producing #enzyme known as #phosphoglycerate #kinase (PGK1). In fact, these latest preclinical findings in models of the disease suggest that boosting this enzyme in the brain even slightly may be enough to restore energy and afford some protection against #Parkinson’s disease. The surprise came when studies showed the drug terazosin, which is used to treat high blood pressure and enlarged prostate, has an unexpected side effect: it enhances PGK1 activity, although perhaps weakly. Could the boost in PGK1 activity be enough to fuel and protect dopamine-producing neurons? Studies in Parkinson’s models including mice, rats, flies, and human cells treated with #terazosin suggested that it could. A retrospective study in people taking terazosin for an enlarged prostate also showed that those taking the drug were less likely to develop Parkinson’s. The researchers report that the increases in PGK1 they saw were enough to protect neurons carrying mutations in genes with known links to familial forms of Parkinson’s disease. They found that effects of a PGK1 boost also depend on another protein, called DJ-1, which has also been implicated in Parkinson’s disease. When the researchers experimentally increased PGK1 levels in mouse models of the disease, it strongly protected their dopamine neurons. Read ➡️ https://lnkd.in/ejRJZ3ZP #parkinsonsdisease

📄 As a macrophage-lover, I couldn’t not share this interesting piece of science! Enjoy the read! #macrophage #plasticity #immunesystem

#NeuroInflammation | #AutoImmuneDisease | #AutoAntibodies | #SLE | Spotlight on how #ACEinhibitors impact #Microlgia to reverse #Memory Loss in #NeuroPsychiatric #Lupus | Online Now at Nature #Immunology | “DNA-targeting autoantibodies, linked to neuropsychiatric manifestations in lupus patients, damage hippocampal neurons by engaging excitotoxic receptors. The authors demonstrate that a danger signal produced by surviving neurons activates microglia, causing sustained neuroinflammation. Upregulation of the angiotensin receptor, C1q and IL-10 and downregulation of the C1q receptor in activated microglia compromised dendritic arborization. Importantly, a brain-acting inhibitor of angiotensin-converting enzyme reversed the process, offering a much-needed therapeutic tool.” Expert Opinion from George Tsokos. [Celentyx Ltd offers #human #microglia #drugdiscovery #platforms to advance #clinical #translation of #neuroinflammation #neurodegeneration #research programmes https://lnkd.in/eMWCkkDw] Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady GRAPHICAL ABSTRACT | Exposure of hippocampal neurons to DNRAbs results in the excitotoxic death of 20–30% of neurons. Maladaptive homeostasis begins as microglia respond to neuronal debris and stressed neurons secrete HMGB1, which activates microglia by binding to RAGE. Activated microglia secrete proinflammatory cytokines, C1q and IL-10 in response, and upregulate ATR1. HMGB1 and C1q tag synaptic proteins for microglia-dependent loss of neuronal dendrite branching. IL-10 suppresses LAIR-1 expression on microglia. Treatment with an ACE inhibitor (ACEi) or ARB decreases the proinflammatory ATII–AT1R signal, and this restores microglial LAIR-1 expression and quiescence, enabling a return to healthy homeostasis and regrowth of dendrites. Figure created with BioRender © 2024, Kaitlin Carroll et al.