Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 46 - 60

Published: July 25, 2023

Language: Английский

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Sphingolipids in neurodegenerative diseases

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Feb. 16, 2023

Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits neuronal function. Recent evidence argues sphingolipid metabolism is affected in surprisingly broad set NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well forms amyotrophic lateral sclerosis (ALS) Parkinson’s disease (PD). Many these have been modeled Drosophila melanogaster associated with elevated levels ceramides. Similar changes also reported vertebrate cells mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature defects metabolism, organelles implicated, cell types initially affected, potential therapeutics for diseases.

Language: Английский

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Focusing on mitochondria in the brain: from biology to therapeutics

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: April 17, 2024

Abstract Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to physiology pathology of many organs tissues, among which brain is particularly prominent. The demands 20% resting metabolic rate holds highly active mitochondrial activities. Considerable research shows that mitochondria function, while defects induce or exacerbate in brain. In this review, we provide comprehensive advances biology involved functions, well mitochondria-dependent cellular events pathology. Furthermore, various perspectives explored better identify roles neurological diseases neurophenotypes diseases. Finally, therapies discussed. Mitochondrial-targeting therapeutics showing great potentials treatment

Language: Английский

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How do sphingosine-1-phosphate affect immune cells to resolve inflammation?

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 28, 2024

Inflammation is an important immune response of the body. It a physiological process self-repair and defense against pathogens taken up by biological tissues when stimulated damage factors such as trauma infection. main cause high morbidity mortality in most diseases basis disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at inflammatory site, reduce complications, mortality. Sphingosine-1-phosphate (S1P), lipid signaling molecule, involved cell transport binding to S1P receptors (S1PRs). plays key role innate adaptive responses closely related inflammation. In homeostasis, lymphocytes follow concentration gradient from into circulation. One widely accepted mechanism that during response, altered, are blocked entering circulation are, therefore, unable reach site. However, full its involvement inflammation not fully understood. This review focuses on bacterial viral infections, autoimmune diseases, immunological aspects Sphks/S1P/S1PRs pathway, highlighting their promoting intradial-adaptive interactions. How regulated how shapes through cells explained detail. We teased apart composition critical pathway modulators host system. By understanding pathogenesis we linked genomic studies S1P-targeted drugs provide for targeted drug development.

Language: Английский

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The murine retinal pigment epithelium requires peroxisomal β-oxidation to maintain lysosomal function and prevent dedifferentiation

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(43)

Published: Oct. 20, 2023

Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but mechanisms involved in digestion and recycling POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play essential role, this never investigated. Here, we show global as well RPE-selective loss peroxisomal β-oxidation multifunctional protein 2 (MFP2) knockout mice impairs digestive function lysosomes RPE at very early age, followed by degeneration. This accompanied prolonged mammalian target rapamycin activation, lipid deregulation, mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The degeneration caused secondary death. Notably, deterioration did not occur Mfp2/rd1 mutant mouse line, characterized absent shedding. Our findings prove is for handling polyunsaturated fatty acids present ingested light retinopathy patients with disorders. data also implications gene therapy development they highlight importance targeting addition cells.

Language: Английский

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Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(37)

Published: Sept. 5, 2023

A hallmark of multiple sclerosis (MS) is the formation focal demyelinating lesions within central nervous system (CNS). These mainly consist phagocytes that play a key role in lesion progression and remyelination, therefore represent promising therapeutic target MS. We recently showed unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell during demyelination. are elongated “elongation very long chain acids” proteins (ELOVLs), generating series functionally distinct lipids. Here, we show expression activity ELOVLs altered myelin-induced cells. Especially ELOVL6, an enzyme responsible for converting saturated monounsaturated C16 into C18 species, was found to be up-regulated myelin phagocytosing vitro MS lesions. Depletion Elovl6 induced repair-promoting phagocyte phenotype through activation S1P/PPARγ pathway. -deficient foamy macrophages enhanced ABCA1-mediated lipid efflux, increased production neurotrophic factors, reduced mediators. Moreover, our data ELOVL6 hampers CNS repair, as deficiency prevented demyelination boosted remyelination organotypic brain slice cultures mouse cuprizone model. findings indicate targeting may effective strategy stimulate repair other neurodegenerative diseases.

Language: Английский

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Mouse serum albumin induces neuronal apoptosis and tauopathies

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: April 23, 2024

Abstract The elderly frequently present impaired blood–brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, most abundant protein in plasma, leaking through disrupted BBB, contributes to neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes A1 phenotype remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis endoplasmic reticulum stress response pathway. Moreover, MSA-activated triggered remarkable tau phosphorylation at multiple sites NLRP3 inflammasome Intracerebroventricular injection MSA into brains C57BL/6J mice a similar concentration as patient apoptosis, neuroinflammation, increased phosphorylation, decreased spatial learning memory abilities, while Elovl1 knockdown prevented deleterious effect MSA. Overall, our study revealed neuron apoptosis based on astrocytes, respectively, showing critical roles initiating occurrence tauopathies cognitive decline, providing potential therapeutic targets MSA-induced disorders.

Language: Английский

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Palmitate-induced mitochondrial damage restricts histone acetylation in CD8+ T cells to impair anti-tumor immunity.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

ABSTRACT Accumulation of lipids in the tumor microenvironment (TME) is a feature several solid tumors and increased palmitate (PA) availability fosters progression metastases. The intrinsic effects PA on cancer cells are well understood, but its role modulating CD8 + T (CTL) functional performances remains elusive. Here, we found that alters mitochondrial metabolism CTL prevents their effector functions an irreversible manner, resulting impaired antitumoral immunity. Mechanistically, PA-induced block demotes histone acetylation chromatin accessibility decrease transcription genes promoting DNA replication production molecules. We identified metabolic enzyme Sphingosine Kinase 2 (SPHK2) as molecular target establishing dysfunction. Consistently, pharmacological inhibition SPHK2 restored fitness, anti-tumor potential. Thus, reveal critical function by undermining antitumor immunity highlight therapeutic potential inhibiting activity to optimize cell functionality.

Language: Английский

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Immunomodulatory effect of efferocytosis at the maternal–fetal interface

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 27, 2025

Abstract Efferocytosis is a mechanism by which phagocytes efficiently clear apoptotic cells, averting their secondary necrosis and the subsequent release of potentially immunogenic or cytotoxic substances that can trigger strong immune inflammatory responses. During efferocytosis, metabolic pathways are transformed, which, along with catabolism cargo, affect function state. Extensive apoptosis occurs during placental development, some studies reported immunomodulatory effects efferocytosis at maternal–fetal interface. The dysregulation strongly linked to pregnancy complications such as preeclampsia recurrent spontaneous abortion. In this review, we discuss mechanisms its relationships metabolism inflammation. We also highlight roles professional non-professional in interface impact on outcomes explore relevant regulatory factors. These insights expected guide future basic research clinical strategies for identifying efferocytosis-related molecules potential predictors therapeutic targets obstetric diseases.

Language: Английский

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Transcriptomics, lipidomics, and single-nucleus RNA sequencing integration: exploring sphingolipids in MASH-HCC progression

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 8, 2025

Abstract Background & aims Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses various conditions, ranging from simple steatosis to metabolic steatohepatitis (MASH) and cirrhosis. MASLD is a significant risk factor for hepatocellular carcinoma (HCC) rapidly becoming the primary cause of transplantation. Dysregulated sphingolipid metabolism has been linked development MASH-HCC. However, detailed insight into profiles cell type-specific changes in key genes involved remains limited forms focus this study. Approaches results This study used well-characterized diet-induced MASH-HCC mouse model (DIAMOND). Total RNA sequencing data, NanoString nCounter ® Gene profiling, single-nucleus (snRNA-seq) GEO data (GSE225381) were characterizing gene regulation progression. Sphingolipids serum profiled using targeted lipidomics. analysis showed dysregulation metabolism, including ceramide synthase 6 (Cers6), serine palmitoyltransferase long chain base subunit 2 (Sptlc2), sphingosine kinase (SphK2), sphingosine-1-phosphate receptor 1–3 (S1pr1-3) which paralleled composition levels both liver. Furthermore, TCGA-LIHC patient analyzed potential prognostic identified univariate multivariate Cox analysis. The underscored significance several related CERS6, SPTLC2, S1PR1. Conclusion Our findings provided valuable insights role sphingolipids progression MASH HCC. Specific may serve as biomarkers diagnosis prognosis

Language: Английский

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