Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 14, 2022

Mitochondrial defects are tightly linked to axon degeneration, yet the underlying cellular mechanisms remain poorly understood. In Caenorhabditis elegans, PVQ axons that lack mitochondria degenerate spontaneously with age. Using an unbiased genetic screen, we found cell-specific activation of CaMKII/UNC-43 suppresses degeneration due loss mitochondria. Unexpectedly, activates conserved Sarm1/TIR-1-ASK1/NSY-1-p38 MAPK pathway and eventually transcription factor CEBP-1 protect against degeneration. addition, show disrupting a trafficking complex composed calsyntenin/CASY-1, Mint/LIN-10, kinesin Further analysis indicates disruption this CaMKII-Sarm1-MAPK through L-type voltage-gated calcium channels. Our findings identify CaMKII as pivot point between mitochondrial describe how it is regulated, uncover surprising neuroprotective role for Sarm1-p38 in context.

Language: Английский

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Gold Nanostrip Array‐Mediated Wireless Electrical Stimulation for Accelerating Functional Neuronal Differentiation

Advanced Science, Journal Year: 2022, Volume and Issue: 9(22)

Published: May 26, 2022

Neural stem cell (NSC)-based therapy holds great promise for the treatment of neurodegenerative diseases. Presently, however, it is hindered by poor functional neuronal differentiation. Electrical stimulation considered one most effective ways to promote differentiation NSCs. In addition surgically implanted electrodes, traditional electrical includes wires connected external power supply, and an additional surgery required remove electrodes or following stimulation, which may cause secondary injuries infections. Herein, a novel method reported generation wireless signals on Au nanostrip array leveraging effect electromagnetic induction under rotating magnetic field. The intensity generated depends rotation speed field strength. array-mediated electric promotes NSC into mature neurons within 5 days, at mRNA, protein, function levels. rate faster least days than that in cells without treatment. array-based device also accelerates NSCs vivo. accelerate has advantages wireless, timely, localized precise controllability, noninvasive supplementation.

Language: Английский

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Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(2), P. 587 - 597

Published: Jan. 31, 2024

JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival injured neurons. However, a poor integration rate and high risk tumorigenicity after cell limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection regeneration. Previous shown stem/progenitor cell-derived sEVs can promote recovery neurological function in neurodegenerative eye diseases other diseases. In this study, we intravitreally transplanted derived from human induced pluripotent stem (hiPSCs) hiPSCs-differentiated NPCs (hiPSC-NPC) mouse model optic nerve crush. Our results show these injected were ingested by retinal cells, especially those localized ganglion layer. Treatment with hiPSC-NPC-derived mitigated crush-induced degeneration, regulated microenvironment inhibiting excessive activation microglia. Component analysis further revealed hiPSC-NPC transported neuroprotective anti-inflammatory miRNA cargos to target which had protective effects on RGCs injury. These findings suggest are promising cell-free therapeutic strategy neuropathy.

Language: Английский

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Intercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 11, 2024

Previous studies of neuronal survival have primarily focused on identifying intrinsic mechanisms controlling the process. This study explored how intercellular communication contributes to retinal ganglion cell (RGC) following optic nerve crush based single-cell RNA-seq analysis. We observed transcriptomic changes in cells response injury, with astrocytes and Müller glia having most interactions RGCs. By comparing RGC subclasses characterized by distinct resilience death, we found that high-survival RGCs tend more ligand-receptor neighboring cells. identified 47 stronger RGCs, likely mediating neuroprotective effects. validated one target, μ-opioid receptor (Oprm1), be three injury models. Although endogenous Oprm1 is preferentially expressed intrinsically photosensitive its effect can transferred other pan-RGC overexpression Oprm1. Lastly, manipulating activity improved visual functions mice.

Language: Английский

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Ca²⁺/Calmodulin-Dependent Protein Kinase II Enhances Retinal Ganglion Cell Survival But Suppresses Axon Regeneration after Optic Nerve Injury

eNeuro, Journal Year: 2024, Volume and Issue: 11(3), P. ENEURO.0478 - 23.2024

Published: March 1, 2024

Neuroprotection after injury or in neurodegenerative disease remains a major goal for basic and translational neuroscience. Retinal ganglion cells (RGCs), the projection neurons of eye, degenerate optic neuropathies axon injury, there are no clinical therapies to prevent their loss restore connectivity targets brain. Here we demonstrate profound neuroprotective effect exogenous expression various Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) isoforms mice. A dramatic increase RGC survival following nerve trauma was elicited by constitutively active variants multiple CaMKII RGCs using adeno-associated viral (AAV) vectors across 100-fold range AAV dosing vivo. Despite this neuroprotection, however, short-distance sprouting suppressed CaMKII, long-distance regeneration several pro-axon growth treatments likewise inhibited even as further enhanced survival. Notably, dose-escalation study, AAV-expressed more potent suppression than promotion That diffuse overexpression strongly promotes may be clinically valuable neuroprotection per se. However, associated strong demonstrates need understanding intracellular domain- target-specific activities development signaling pathway-directed strategies treatment neuropathies.

Language: Английский

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The neuroprotective effect of melatonin in glutamate excitotoxicity of R28 cells and mouse retinal ganglion cells

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 12, 2022

Glaucoma is the leading cause of irreversible blindness. The progressive degeneration retinal ganglion cells (RGCs) major characteristic glaucoma. Even though control intraocular pressure could delay loss RGCs, current clinical treatments cannot protect them directly. overactivation N-methyl-D-aspartic acid (NMDA) receptors by excess glutamate (Glu) among important mechanisms RGC death in glaucoma progression. Melatonin (MT) an indole neuroendocrine hormone mainly secreted pineal gland. This study aimed to investigate therapeutic effect MT on excitotoxicity mouse RGCs and R28 cells. Glu-induced cell model NMDA-induced injury were established. was applied vitreous cavity mice intravitreal injection. Cell counting kit-8 assay propidium iodide/Hoechst performed evaluate viability. Reactive oxygen species glutathione synthesis assays used detect oxidative stress state Retina immunofluorescence hematoxylin eosin staining assess counts structure. Flash visual-evoked potential visual function mice. RNA sequencing retina explore underlying protection. Our results found that treatment successfully from Glu decrease reactive species. Also, rescued protected enriches indications glaucoma, providing practical research ideas for its comprehensive prevention treatment.

Language: Английский

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Neuroprotection in Glaucoma: Basic Aspects and Clinical Relevance

Journal of Personalized Medicine, Journal Year: 2022, Volume and Issue: 12(11), P. 1884 - 1884

Published: Nov. 10, 2022

Glaucoma is a neurodegenerative disease that affects primarily the retinal ganglion cells (RGCs). Increased intraocular pressure (IOP) one of major risk factors for glaucoma. The mainstay current glaucoma therapy limited to lowering IOP; however, controlling IOP in certain patients can be futile slowing progression. understanding potential biomolecular processes occur glaucomatous degeneration allows development treatments modulate death RGCs. Neuroprotection modification RGCs and microenvironment neurons promote neuron survival function. Numerous studies have revealed effective neuroprotection modalities animal models glaucoma; nevertheless, clinical translation remains challenge. In this review, we select most clinically relevant treatment strategies, summarize preclinical data as well recent therapeutic advances IOP-independent research, discuss feasibility hurdles each approach based on possible pathogenic mechanisms. We also mechanisms various agents related glutamate excitotoxicity.

Language: Английский

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Neuroprotection of SRT2104 in Murine Ischemia/Reperfusion Injury Through the Enhancement of Sirt1-Mediated Deacetylation

Investigative Ophthalmology & Visual Science, Journal Year: 2023, Volume and Issue: 64(4), P. 31 - 31

Published: April 26, 2023

Purpose: Strategies for neuroprotection are the main targets of glaucoma research. The neuroprotective properties SRT2104 administration have been proven in central nervous system degeneration diseases through activation nicotinamide adenine dinucleotide-dependent deacetylase-silence information regulator 1 (Sirt1). Here, we investigated whether could protect retina from ischemia/reperfusion (I/R) injury and underlying mechanisms. Methods: was intravitreally injected immediately after I/R induction. RNA protein expression were detected by quantitative real-time PCR Western blot. Protein distribution examined immunofluorescence staining. Retinal structure function analyzed hematoxylin eosin staining, optical coherence tomography, electroretinogram. Optic nerve axons quantified using toluidine blue Cellular apoptosis senescence evaluated TUNEL assay SA-β-gal Results: Sirt1 decreased dramatically effectively enhanced stability without significantly influencing mRNA synthesis. alone exerted no influence on normal retinas. However, intervention protected inner retinal neurons; partially restored injury. I/R-induced cellular alleviated administration. Additionally, markedly reduced neuroinflammation, including reactive gliosis, vascular inflammation, overexpression pro-inflammatory cytokines Mechanistically, acetylation p53, NF-κB p65, STAT3 reversed intervention. Conclusions: We demonstrated that potent protective effects against enhancing Sirt1-mediated deacetylation suppressing apoptosis, senescence, neuroinflammation-related pathways.

Language: Английский

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Rapamycin suppresses neuroinflammation and protects retinal ganglion cell loss after optic nerve crush

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 119, P. 110171 - 110171

Published: April 14, 2023

Language: Английский

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Schwann cell–derived extracellular vesicles as a potential therapy for retinal ganglion cell degeneration

Journal of Controlled Release, Journal Year: 2023, Volume and Issue: 363, P. 641 - 656

Published: Oct. 13, 2023

Optic neuropathy is the leading cause of irreversible blindness and characterized by progressive degeneration retinal ganglion cells (RGCs). Several studies have demonstrated that transplantation Schwann (SCs) a promising candidate therapy for optic intravitreally transplanted exert their effect via paracrine actions. Extracellular vesicle (EV)-based therapies are increasingly recognized as potential strategy cell replacement therapy. In this study, we aimed to investigate neuroprotective regenerative effects SC-EVs following nerve injury. We found were internalized RGCs in vitro vivo without any transfection reagents. Intriguingly, significantly enhanced survival axonal growth primary coculture system. rat crush model, mitigated RGC degeneration, prevented loss, preserved thickness complex, statistically significant improvement counts measurements. Mechanistically, activated cAMP-response element binding protein (CREB) signaling pathway regulated reactive gliosis ONC rats, which crucial protection regeneration. These findings provide novel insights into properties SC-EVs, suggesting cell-free therapeutic natural biomaterials neurodegenerative diseases central nervous

Language: Английский

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