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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Glaucoma: now and beyond

The Lancet, Journal Year: 2023, Volume and Issue: 402(10414), P. 1788 - 1801

Published: Sept. 21, 2023

Language: Английский

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Collagen in the central nervous system: contributions to neurodegeneration and promise as a therapeutic target

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 25, 2024

Abstract The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects governs the physiological status local microenvironment. in central nervous system (CNS) far from simply an inert scaffold for mechanical support, instead conducting active role homeostasis providing broad capacity adaptation remodeling response to stress otherwise would challenge equilibrium between neuronal, glial, vascular elements. A major constituent collagen, whose characteristic triple helical structure renders biochemical stability enable bidirectional crosstalk resident cells. Multiple members collagen superfamily are critical neuronal maturation circuit formation, axon guidance, synaptogenesis brain. In mature tissue, interacts with other fibrous proteins glycoproteins sustain three-dimensional medium through which complex networks cells can communicate. While scaffolding, CNS also highly dynamic, multiple binding sites partnering proteins, cell-surface receptors, ligands. These interactions emerging as mediators disease injury, particularly regarding changes stiffness, astrocyte recruitment reactivity, pro-inflammatory signaling microenvironments. Changes and/or deposition impact cellular tissue biomechanics brain, turn alter responses including antigenicity, angiogenesis, gliosis, immune-related factors, each involving contribute limited regeneration tissue. Emerging therapeutics attempt rebuild using peptide fragments, collagen-enriched scaffolds mimetics, hold great potential promote neural repair regeneration. Recent evidence our group others indicates repairing protease-degraded helices mimetic peptides helps restore survival spectrum degenerative conditions. Restoration likely involves bolstering stiffness reduce reactivity inflammation well inhibitory immune-signaling Facilitating rather than endogenous replacement degraded by or injury may represent next frontier developing therapies based on protection, repair, neurons system.

Language: Английский

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Aging, Cellular Senescence, and Glaucoma

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(2), P. 546 - 546

Published: Jan. 1, 2024

Aging is one of the most serious risk factors for glaucoma, and according to age-standardized prevalence, glaucoma second leading cause legal blindness worldwide. Cellular senescence a hallmark aging that defined by stable exit from cell cycle in response cellular damage stress. The potential mechanisms underlying glaucomatous include oxidative stress, DNA damage, mitochondrial dysfunction, defective autophagy/mitophagy, epigenetic modifications. These phenotypes interact generate sufficiently network maintain senescent state. Senescent trabecular meshwork (TM) cells, retinal ganglion cells (RGCs) vascular endothelial reportedly accumulate with age stress may contribute pathologies. Therapies targeting suppression or elimination have been found ameliorate RGC death improve vision models, suggesting pivotal role pathophysiology glaucoma. In this review, we explore biological links between specifically delving into senescence. Moreover, summarize current data on key target associated development clinical Finally, discuss therapeutic management

Language: Английский

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NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(4), P. 1421 - 1431

Published: Jan. 31, 2022

The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge glaucoma management. Emerging evidence suggests that redox factor NAD+ decline hallmark aging neurodegenerative diseases. Supplementation with precursors overexpression NMNAT1, the key enzyme in biosynthetic process, have significant effects. We first profile translatomes RGCs naive mice silicone oil-induced ocular hypertension (SOHU)/glaucoma by RiboTag mRNA sequencing. Intriguingly, only NMNAT2, but not NMNAT1 or NMNAT3, significantly decreased SOHU glaucomatous RGCs, which we confirm situ hybridization. next demonstrate AAV2 intravitreal injection-mediated long half-life NMNAT2 mutant driven RGC-specific mouse γ-synuclein (mSncg) promoter restores levels ONs. Moreover, this gene therapy strategy delivers neuroprotection both RGC soma axon preservation visual function traumatic ON crush model model. Collectively, our studies suggest weakening expression contributes to deleterious decline, modulating RGC-intrinsic AAV2-mSncg vector promising neurodegeneration.

Language: Английский

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Single-cell transcriptome analysis of regenerating RGCs reveals potent glaucoma neural repair genes

Neuron, Journal Year: 2022, Volume and Issue: 110(16), P. 2646 - 2663.e6

Published: Aug. 1, 2022

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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Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(15), P. 7994 - 7994

Published: July 27, 2021

Retinal ganglion cells (RGCs) are a population of neurons the central nervous system (CNS) extending with their soma to inner retina and axons optic nerve. Glaucoma represents group neurodegenerative diseases where slow progressive death RGCs results in permanent loss vision. To date, although Intra Ocular Pressure (IOP) is considered main therapeutic target, precise mechanisms by which die glaucoma have not yet been clarified. In fact, Primary Open Angle (POAG), most common form, also occurs without elevated IOP. This present review provides summary some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity changes pro-inflammatory cytokines along RGC projection, all involved cascade. Moreover, neuro-protective approaches, aim improve degeneration, taken into consideration.

Language: Английский

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The Interaction Between Microglia and Macroglia in Glaucoma

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: May 28, 2021

Glaucoma, a neurodegenerative disease that leads to irreversible vision loss, is characterized by progressive loss of retinal ganglion cells (RGCs) and optic axons. To date, elevated intraocular pressure (IOP) has been recognized as the main phenotypic factor associated with glaucoma. However, some patients normal IOP also have glaucomatous visual impairment RGC loss. Unfortunately, underlying mechanisms behind such cases remain unclear. Recent studies suggested glia play significant roles in initiation progression Multiple types glial are activated Microglia, for example, act critical mediators orchestrate neuroinflammation through pro-inflammatory cytokines. In contrast, macroglia (astrocytes Müller cells) participate inflammatory responses modulators contribute neuroprotection secretion neurotrophic factors. Notably, research results indicated intricate interactions between microglia might provide potential therapeutic targets prevention treatment this review, we examine specific open-angle glaucoma, including glaucoma animal models, analyze interaction these two cell types. addition, discuss options based on relationship neurons.

Language: Английский

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Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 32, P. 13 - 27

Published: Feb. 27, 2023

Optic neuropathy is a group of optic nerve (ON) diseases with progressive degeneration ON and retinal ganglion cells (RGCs). The lack neuroprotective treatments central challenge for this leading cause irreversible blindness. SARM1 (sterile α TIR motif-containing protein 1) has intrinsic nicotinamide adenine dinucleotide (NAD+) hydrolase activity that causes axon by degrading axonal NAD+ significantly after activation injury. deletion in many, but not all, neurodegenerative disease models. Here, we compare two therapy strategies inhibition, antisense oligonucleotide (ASO) CRISPR, germline the neuroprotection three mouse This study reveals that, similar to knockout every cell, local ASO delivery adeno-associated virus (AAV)-mediated RGC-specific CRISPR knockdown provide comparable both RGC somata axons silicone oil-induced ocular hypertension (SOHU) glaucoma model only protect axons, somata, traumatic Surprisingly, neither these inhibition nor (KO) benefits or survival experimental autoimmune encephalomyelitis (EAE)/optic neuritis model. Our studies therefore suggest AAV-mediated promising gene strategy glaucomatous neuropathies demyelinating neuritis.

Language: Английский

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