CIB2 regulates autophagy via Rheb-mTORC1 signaling axis

SUMMARYAge-related macular degeneration (AMD), a multifactorial neurodegenerative disorder, is the most common cause of vision loss in the elderly. Deficits in autophagy have been associated with age-related retinal pigment epithelium (RPE) pathology in mice, and dry-AMD in humans. In this study, we establish that the calcium and integrin binding protein 2 (CIB2) regulates autophagy in the RPE via Rheb-mTORC1 signaling axis. Cib2 mutant mice have reduced autophagic clearance in RPE and increased mTORC1 signaling – a negative regulator of autophagy. Concordant molecular deficits were also observed in RPE/choroid tissues from humans affected with dry AMD. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in aging, Tuberous sclerosis complex (TSC), and lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts and Tsc2 null cell line down-regulates hyperactive mTORC1 signaling. Thus, our findings have significant ramifications for the etiology of AMD and mTORC1 hyperactivity disorders and treatments.

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CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

Nature Communications ◽

10.1038/s41467-021-24056-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Saumil Sethna ◽

Patrick A. Scott ◽

Arnaud P. J. Giese ◽

Todd Duncan ◽

Xiaoying Jian ◽

...

Keyword(s):

Visual Function ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Negative Regulator ◽

Age Related Macular Degeneration ◽

Age Related ◽

Mtorc1 Signaling ◽

Marked Accumulation

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

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Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2021-000774 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000774

Author(s):

Minwei Wang ◽

Shiqi Su ◽

Shaoyun Jiang ◽

Xinghuai Sun ◽

Jiantao Wang

Keyword(s):

Mitochondrial Dysfunction ◽

Macular Degeneration ◽

Vision Loss ◽

Cell Structure ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Amyloid Β ◽

Age Related Macular Degeneration ◽

Amyloid Β Peptide ◽

Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms19082317 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2317 ◽

Cited By ~ 32

Author(s):

Kai Kaarniranta ◽

Jakub Kajdanek ◽

Jan Morawiec ◽

Elzbieta Pawlowska ◽

Janusz Blasiak

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Mitochondrial Biogenesis ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Sirtuin 1 ◽

Age Related Macular Degeneration ◽

Rpe Cells ◽

Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

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The Effects of Indocyanine Green Dye-Enhanced Photocoagulation on the Blood Flow in the Choriocapillaris and the Choroidal Neovascularization (CNV)

10.1115/imece2000-2213 ◽

2000 ◽

Author(s):

C. von Kerczek ◽

L. Zhu ◽

A. Ernest ◽

C. Eggleton ◽

L. D. T. Topoleski ◽

...

Keyword(s):

Laser Treatment ◽

Choroidal Neovascularization ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The United States ◽

Age Related Macular Degeneration ◽

Central Vision ◽

Age Related ◽

Direct Laser

Abstract Age-related macular degeneration (AMD) is the most common cause of vision loss in patients aged 65 years and older in the United States. In the majority of cases, the loss of central vision is secondary to exudative changes and fibrovascular scarring following choroidal neovascularization (CNV). Prompt laser treatment is recommended [Asrani et al., 1996; Macular Photocoagulation Study Group, 1993; Schneider et al, 1998]. However, direct laser treatment to the entire subfoveal lesion is almost invariably associated with immediate loss of central vision. Loss of central vision may be due to direct damage to foveal photoreceptors and retinal pigment epithelium or from damage to the nerve fiber layer serving foveal function [Han et al., 1988].

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Apolipoprotein E isoform-specific phase transitions in the retinal pigment epithelium drive disease phenotypes in age-related macular degeneration

10.1101/2020.07.15.201723 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nilsa La Cunza ◽

Li Xuan Tan ◽

Gurugirijha Rathnasamy ◽

Thushara Thamban ◽

Colin J. Germer ◽

...

Keyword(s):

Phase Transitions ◽

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Human Donor ◽

Age Related ◽

Histopathological Studies

AbstractThe retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.

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Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Journal of Neuroinflammation ◽

10.1186/s12974-021-02088-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Keng Siang Lee ◽

Shuxiao Lin ◽

David A. Copland ◽

Andrew D. Dick ◽

Jian Liu

Keyword(s):

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Cellular Senescence ◽

Vision Loss ◽

Inflammatory Responses ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Age Related

AbstractAge-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

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Saponin-Mediated Rejuvenation of Bruch’s Membrane: A New Strategy for Intervention in Dry Age-Related Macular Degeneration (AMD)

10.5772/intechopen.96818 ◽

2021 ◽

Author(s):

Yunhee Lee ◽

Eun Jung Ahn ◽

Ali Hussain

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Bruch's Membrane ◽

Bruch’S Membrane ◽

Age Related ◽

New Strategy ◽

The Matrix ◽

Dry Amd ◽

Underlying Mechanisms

At present, there is no treatment modality for the vast majority of patients with dry AMD. The pathophysiology of AMD is complex but current evidence suggests that abnormal ageing of Bruch’s membrane imparts a metabolic insult to the retinal pigment epithelium (RPE) and photoreceptor cells that leads eventually to the inflammatory-mediated death of these cells. Underlying mechanisms contributing to the pathology of Bruch’s membrane include the accumulation of ‘debris’ and malfunction of the matrix metalloproteinase (MMP) system resulting in diminished metabolic support of the retina and inefficient removal of toxic pro-inflammatory mediators. Saponins are amphipathic molecules that have a hydrophobic tri-terpenoid lipid region and hydrophilic glycosidic chains that allow for the dispersion of these deposits in Bruch’s and re-activation of the MMP system leading to a 2-fold improvement in the transport properties of the membrane. Such an intervention is expected to improve the bi-directional exchange of nutrients and waste products, thereby slowing the progression of dry AMD. This will be the first drug-based interventionist possibility to address dry AMD.

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Classical, Micropulse and NanoSecond Laser Therapy in Dry-Form (Non-Neovascular) Age-Related Macular Degeneration

Güncel Retina Dergisi (Current Retina Journal) ◽

10.37783/crj-0026 ◽

2017 ◽

pp. 155-159

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Treatment Modalities ◽

Nanosecond Laser ◽

Laser Applications ◽

Age Related ◽

Neuroprotective Treatment

Age-related macular degeneration (AMD), which is a multifactorial, degenerative disease of the retina, is the most common reason for legal blindness over 50 years of age. Dry-form (non-neovascular) AMD is the common type, and frequently non-progressive to total vision loss. Epidemiological, histopathological, and biochemical data demonstrate that AMD is associated with oxidative damage, lipofuscin accumulation, chronic inflammation, and mutations in the complement system. Drusen, hyperpigmentation/hypopigmentation in retinal pigment epithelium, and geographical atrophy can also be observed in dry-form AMD. Various treatment modalities can be used according to the stages of the disease. Antioxidants, visual cycle inhibitors, anti-inflammatory agents, neuroprotective treatment, conventional, micropulse, and nano-second laser applications are intended to regulate the various mechanisms involved in the pathogenesis of the disease.

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Cell Stiffening Contributes to Complement-mediated Injury of Choroidal Endothelial Cells in Early AMD

10.1101/2021.10.06.463274 ◽

2021 ◽

Author(s):

Andrea P Cabrera ◽

Jonathan Stoddard ◽

Irene Santiago Tierno ◽

Nikolaos Matisioudis ◽

Mahesh Agarwal ◽

...

Keyword(s):

Endothelial Cells ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Membrane Attack Complex ◽

Small Gtpases ◽

Age Related Macular Degeneration ◽

Cell Stiffness ◽

Age Related ◽

Dry Amd ◽

Choroidal Vessels

Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Yet, no therapies exist for ~85% of all AMD patients who have the dry form that is marked by degeneration of the retinal pigment epithelium (RPE) and underlying choroidal vasculature. As the choroidal vessels are crucial for RPE development and maintenance, understanding how they degenerate may lead to effective therapies for dry AMD. One likely causative factor for choroidal vascular loss is the cytolytic membrane attack complex (MAC) of the complement pathway that is abundant on choroidal vessels of humans with early dry AMD. To examine this possibility, we studied the effect of complement activation on choroidal endothelial cells (ECs) isolated from a rhesus monkey model of early AMD that, we report, exhibits MAC deposition and choriocapillaris endothelial loss similar to that seen in human early AMD. Treatment of choroidal ECs from AMD eyes with complement-competent normal human serum caused extensive actin cytoskeletal injury that was significantly less pronounced in choroidal ECs from young normal monkey eyes. We further show that ECs from AMD eyes are significantly stiffer than their younger counterparts and exhibit peripheral actin organization that is distinct from the longitudinal stress fibers in young ECs. Finally, these differences in complement susceptibility and mechanostructural properties were found to be regulated by the differential activity of small GTPases Rac and Rho because Rac inhibition in AMD cells led to simultaneous reduction in stiffness and complement susceptibility while Rho inhibition in young cells exacerbated complement injury. Thus, by identifying cell stiffness and cytoskeletal regulators Rac and Rho as important determinants of complement susceptibility, the current findings offer a new mechanistic insight into choroidal vascular loss in early AMD that warrants further investigation for assessment of translational potential.

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Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model

Nature Communications ◽

10.1038/s41467-021-27488-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ruchi Sharma ◽

Aman George ◽

Malika Nimmagadda ◽

Davide Ortolan ◽

Barbosa-Sabanero Karla ◽

...

Keyword(s):

Macular Degeneration ◽

High Throughput Screening ◽

Vision Loss ◽

Risk Allele ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Age Related ◽

Epithelial Phenotype ◽

Rpe Atrophy

AbstractAge-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.

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