Solving neurodegeneration: common mechanisms and strategies for new treatments

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

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Impaired axonal transport contributes to neurodegeneration in a Cre-inducible mouse model of myocilin-associated glaucoma

JCI Insight, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading neurodegeneration, is the pathological hallmark primary open-angle glaucoma (POAG). Impaired axonal transport an early and critical feature glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking. We report development characterization novel Cre-inducible expressing DsRed-tagged Y437H mutant myocilin (Tg.CreMYOCY437H). A single intravitreal injection HAd5-Cre induced selective MYOC expression in TM, causing TM reducing outflow facility, progressively elevating IOP Tg.CreMYOCY437H mice. Sustained elevation resulted significant loss retinal ganglion cells (RGCs) progressive degeneration Cre-induced Notably, impaired anterograde was observed at optic nerve head before RGC degeneration, independent age, indicating contributes In contrast, remained intact ocular hypertensive mice injected with microbeads, despite loss. Our findings indicate replicate all phenotypes, providing ideal for studying events dysfunction neuronal POAG.

Language: Английский

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Retina in a dish: Cell cultures, retinal explants and animal models for common diseases of the retina

Progress in Retinal and Eye Research, Journal Year: 2020, Volume and Issue: 81, P. 100880 - 100880

Published: July 25, 2020

Language: Английский

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Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: July 21, 2021

Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial signaling can exacerbate issues chronic This review discusses for the interaction damage inflammation, with a focus on glaucomatous neurodegeneration, proposes that positive feedback resulting from this drives pathology. exacerbates multiple ways. Damaged DNA is damage-associated molecular pattern, which activates NLRP3 inflammasome; priming activation of inflammasome, liberation IL-1β IL-18 via gasdermin D pore, major pathway enhance responses. The rise reactive oxygen species induced by also pathways, while blockage Complex enzymes increase signaling. Impaired mitophagy contributes inflammation as inability turnover mitochondria timely manner increases levels ROS mtDNA, latter likely stimulate cGAS-STING interferon associated ER membrane contacts mitochondria-associated adaptor molecule MAVS activate inflammasome In addition dysfunctional increasing corollary occurs, reducing function ATP production; downward spiral accelerates degeneration. Evidence several preclinical models including DBA/2J mouse, microbead injection transient elevation IOP, patient data, implicates neurodegeneration. pressure-dependent hypoxia metabolic vulnerability release. Links occur retinal ganglion cells, microglia cells astrocytes. summary, increased enhances implications other complex neurodegenerations like Alzheimer’s Parkinson’s disease.

Language: Английский

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Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms

Investigative Ophthalmology & Visual Science, Journal Year: 2022, Volume and Issue: 63(2), P. 12 - 12

Published: Feb. 7, 2022

Due to their similarities in anatomy, physiology, and pharmacology humans, mice are a valuable model system study the generation mechanisms modulating conventional outflow resistance thus intraocular pressure. In addition, mouse models critical for understanding complex nature of homeostasis dysfunction that results ocular hypertension. this review, we describe set minimum acceptable standards developing, characterizing, utilizing open-angle We expect standard practices will increase scientific rigor when using better enable researchers replicate build upon previous findings.

Language: Английский

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Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

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

Published: Sept. 21, 2023

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach reverse from if newly introduced neurons can reestablish functional retinal thalamic circuits. In theory, RGCs might be repopulated through transplantation of stem cell-derived or via induction endogenous transdifferentiation. The Repopulation, Stem Cell Transplantation, Optic Nerve Regeneration (RReSTORe) Consortium was established address challenges associated with repair visual pathway neuropathy. 2022, RReSTORe initiated ongoing international collaborative discussions advance field has identified five critical areas focus: (1) development differentiation, (2) Transplantation methods models, (3) survival, maturation, host interactions, (4) Inner wiring, (5) Eye-to-brain connectivity. Here, we discuss most pertinent questions that exist on path clinical translation suggest experimental directions propel this work going forward. Using these subtopic discussion groups (SDGs) as framework, multidisciplinary approaches restore diseased by leveraging groundbreaking insights developmental neuroscience, biology, molecular optical imaging, animal models neuropathy, immunology & immunotolerance, neuropathology neuroprotection, materials science biomedical engineering, neuroscience. While significant hurdles remain, Consortium's efforts provide comprehensive roadmap for advancing hold potential transformative progress restoring patients suffering neuropathies.

Language: Английский

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Protective effect of the natural flavonoid naringenin in mouse models of retinal injury

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 962, P. 176231 - 176231

Published: Dec. 3, 2023

Language: Английский

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Addressing neurodegeneration in glaucoma: Mechanisms, challenges, and treatments

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 100, P. 101261 - 101261

Published: March 26, 2024

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration retinal ganglion cell (RGC) projection brain through optic nerve. associated with sensitivity intraocular pressure (IOP). Thus, mainstay treatments seek manage IOP, though many patients continue lose vision. To address directly, numerous preclinical studies develop protective or reparative therapies that act independently IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, neuromodulators. Despite success in experimental models, these approaches fail translate into clinical benefits. Several factors contribute this challenge. Firstly, anatomic structure nerve head differs between rodents, nonhuman primates, humans. Additionally, animal models do not replicate complex glaucoma pathophysiology Therefore, enhance translating findings, we propose two approaches. First, thorough evaluation targets multiple including should precede trials. Second, advocate for combination therapy, which involves using agents simultaneously, especially early potentially reversible stages disease. strategies aim increase chances successful neuroprotective treatment glaucoma.

Language: Английский

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Lung regeneration: diverse cell types and the therapeutic potential

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Abstract Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung can restore normal structure function. Disruptions in this process lead to respiratory system failure even death, causing substantial medical burden. The main types of diseases are chronic obstructive pulmonary disease (COPD), idiopathic fibrosis (IPF), acute distress syndrome (ARDS). Multiple cells, such as epithelial endothelial fibroblasts, immune involved regulating the Although mechanism that regulates not been fully elucidated, clinical trials targeting different cells signaling pathways have achieved some therapeutic effects diseases. In review, we provide an overview cell type regeneration repair, research models, summarize molecular mechanisms regulation fibrosis. Moreover, discuss current stem therapy pharmacological strategies for COPD, IPF, ARDS treatment. This review provides reference further on cellular regeneration, drug development, trials.

Language: Английский

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Lentiviral mediated delivery of CRISPR/Cas9 reduces intraocular pressure in a mouse model of myocilin glaucoma

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 23, 2024

Mutations in myocilin (MYOC) are the leading known genetic cause of primary open-angle glaucoma, responsible for about 4% all cases. MYOC a gain-of-function phenotype which mutant accumulates endoplasmic reticulum (ER) to ER stress and trabecular meshwork (TM) cell death. Therefore, knocking out at genome level is an ideal strategy permanently cure disease. We have previously utilized CRISPR/Cas9 editing successfully target using adenovirus 5 (Ad5). However, Ad5 not suitable vector clinical use. Here, we sought determine efficacy adeno-associated viruses (AAVs) lentiviruses (LVs) TM. First, examined TM tropism single-stranded (ss) self-complimentary (sc) AAV serotypes as well LV expressing GFP via intravitreal (IVT) intracameral (IC) injections. observed that LV_GFP expression was more specific injected IVT route. IC injections Trp-mutant scAAV2 showed prominent robust also ciliary body retina. next constructed lentiviral particles Cas9 guide RNA (gRNA) targeting (crMYOC) transduction cells stably with LV_crMYOC significantly reduced accumulation its associated chronic stress. A single injection Tg-MYOC

Language: Английский

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