Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice DOI
Rui Wang, Hongyang Sun, Yifan Cao

et al.

Science Signaling, Journal Year: 2024, Volume and Issue: 17(829)

Published: March 26, 2024

Mutations in the gene encoding lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and considered strongest genetic risk factor Parkinson’s (PD) Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) cells contributes neuropathology GD, PD, LBD by triggering chronic neuroinflammation. Here, we investigated mechanisms which GC induces We found that within microglia induced pharmacological inhibition triggered STING-dependent inflammation, contributed neuronal loss both vitro vivo. mitochondrial DNA (mtDNA) leakage cytosol trigger inflammation. Rapamycin, a compound promotes activity, improved function, thereby decreasing STING signaling. Furthermore, damage caused led defects degradation activated STING, further exacerbating inflammation mediated microglia. Thus, limiting activity may be strategy suppress neuroinflammation deficiency.

Language: Английский

Lysosomal dysfunction in neurodegeneration: emerging concepts and methods DOI Creative Commons
Vinod Udayar, Yu Chen, Ellen Sidransky

et al.

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(3), P. 184 - 199

Published: Jan. 13, 2022

Language: Английский

Citations

131
Mitochondrial DNA Release in Innate Immune Signaling DOI Creative Commons
Laura Newman, Gerald S. Shadel

Annual Review of Biochemistry, Journal Year: 2023, Volume and Issue: 92(1), P. 299 - 332

Published: March 31, 2023

According to the endosymbiotic theory, most of DNA original bacterial endosymbiont has been lost or transferred nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is present-day mitochondrial (mtDNA). The ability mtDNA escape mitochondria and integrate into nuclear genome was discovered budding yeast, along with genes regulate this process. Mitochondria have emerged as key regulators innate immunity, it now recognized released cytoplasm, outside cell, circulation activates multiple immune signaling pathways. Here, we first review mechanisms through which including several inducible pores defective mitophagy autophagy. Next, cover how different forms activate specific nucleic acid sensors inflammasomes. Finally, discuss intracellular extracellular release, circulating cell-free promotes systemic inflammation, are implicated human diseases, viral infections, senescence aging.

Language: Английский

Citations

97
Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy DOI Creative Commons
Zili Zhang, Haifeng Zhou, Xiaohu Ouyang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 23, 2022

Since the discovery of Stimulator Interferon Genes (STING) as an important pivot for cytosolic DNA sensation and interferon (IFN) induction, intensive efforts have been endeavored to clarify molecular mechanism its activation, physiological function a ubiquitously expressed protein, explore potential therapeutic target in wide range immune-related diseases. With orthodox ligand 2'3'-cyclic GMP-AMP (2'3'-cGAMP) upstream sensor 2'3'-cGAMP synthase (cGAS) be found, STING acquires central functionality best-studied signaling cascade, namely cGAS-STING-IFN pathway. However, recently updated research through structural research, genetic screening, biochemical assay greatly extends current knowledge biology. A second pocket was discovered transmembrane domain synthetic agonist. On downstream outputs, accumulating studies sketch primordial multifaceted roles beyond cytokine-inducing function, such autophagy, cell death, metabolic modulation, endoplasmic reticulum (ER) stress, RNA virus restriction. Furthermore, with expansion interactome, details trafficking also get clearer. After retrospecting brief history viral interference milestone events since STING, we present vivid panorama biology taking into account information, especially versatile outputs functions IFN induction. We summarize pathogenesis various diseases highlight development small-molecular compounds targeting disease treatment combination latest research. Finally, discuss open questions imperative answer.

Language: Английский

Citations

90
Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential DOI Creative Commons
Martin T. Henrich, Wolfgang H. Oertel, D. James Surmeier

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Nov. 11, 2023

Abstract Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, iron chelators, have failed disease-modification clinical trials. In this review, we summarize cellular determinants impairment electron transport chain complex 1, increased oxidative stress, disturbed quality control mechanisms, bioenergetic deficiency. addition, outline pathways to neurodegeneration current context PD pathogenesis, review past treatment an attempt better understand why translational efforts thus far been unsuccessful.

Language: Английский

Citations

90
Mitochondrial signalling and homeostasis: from cell biology to neurological disease DOI Creative Commons
Jack J. Collier, Monika Oláhová, Thomas G. McWilliams

et al.

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(2), P. 137 - 152

Published: Jan. 10, 2023

Efforts to understand how mitochondrial dysfunction contributes neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress understanding etiological nature emerging functions has yielded new ideas about basis neurological disease. Studies aimed at deciphering signal through interorganellar contacts, vesicular trafficking, and metabolic transmission revealed that regulation immunometabolism, cell death, organelle dynamics, neuroimmune interplay are critical determinants neural health. Moreover, homeostatic mechanisms exist protect health turnover via nanoscale proteostasis lysosomal degradation become integrated within signalling pathways support plasticity stress responses nervous system. This review highlights these distinct converge influence contribute disease pathology.

Language: Английский

Citations

70
STING trafficking as a new dimension of immune signaling DOI Creative Commons
Devon Jeltema,

Kennady Abbott,

Nan Yan

et al.

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(3)

Published: Jan. 13, 2023

The cGAS-STING pathway is an evolutionarily conserved immune signaling critical for microbial defense. Unlike other innate pathways that largely rely on stationary cascades of events, STING highly mobile in the cell. activated ER, but only signals after it arrives Golgi, and then quickly degraded by lysosome. Each step trafficking through secretory regulated host factors. Homeostatic via COPI-, COPII-, clathrin-coated vesicles important maintaining baseline tissue cellular immunity. Aberrant vesicular or lysosomal dysfunction produces signal STING, which often leads to pathology mice humans. Many trafficking-mediated diseases appear impact central nervous system, leading neurodegeneration. Therefore, introduces a new dimension likely has broad implications human disease.

Language: Английский

Citations

52
Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism DOI Creative Commons
Zoë P. Van Acker, Anika Perdok, R. Hellemans

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 24, 2023

Abstract Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer’s disease (LOAD). Being a lysosomal 5’-3’ exonuclease, its neuronal substrates remained unknown as well how defective nucleotide catabolism connects AD-proteinopathy. We identified mitochondrial DNA (mtDNA) major physiological substrate and show manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates degradative (proteolytic) bottleneck that presents at the ultrastructural level marked abundance multilamellar bodies, often containing remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage cytosol activates cGAS–STING signaling upregulates autophagy induces amyloid precursor C-terminal fragment (APP-CTF) cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout PLD3-deficient backgrounds lowers activation biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between turnover, cGAS-STING metabolism that, when dysregulated, result endolysosomal demise observed LOAD.

Language: Английский

Citations

48
RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions DOI Creative Commons
Michael G. Hanna, Andrés Guillén-Samander, Pietro De Camilli

et al.

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 409 - 434

Published: July 5, 2023

The life of eukaryotic cells requires the transport lipids between membranes, which are separated by aqueous environment cytosol. Vesicle-mediated traffic along secretory and endocytic pathways lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few at time thought mediate shuttle-like mechanisms. Over last years, new family has been discovered that is defined repeating β-groove (RBG) rod-like structure with hydrophobic channel running their entire length. This localization these membrane contact sites suggest bridge-like mechanism Mutations some result neurodegenerative developmental disorders. Here we review properties well-established putative physiological roles proteins, highlight many questions remain open about functions.

Language: Английский

Citations

48
Lysosomes in senescence and aging DOI
Xiaojun Tan, Toren Finkel

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(11)

Published: Oct. 9, 2023

Language: Английский

Citations

47
The role of PINK1–Parkin in mitochondrial quality control DOI
Derek P. Narendra, Richard J. Youle

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(10), P. 1639 - 1651

Published: Oct. 1, 2024

Language: Английский

Citations

39