Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- or danger-associated molecular pattern. The involvement of TLR activation in AMD is so far not understood. (2) Methods: We performed a systematic literature research, consulting the National Library of Medicine (PubMed). (3) Results: We identified 106 studies, of which 54 were included in this review. Based on these studies, the current status of TLR in AMD, the effects of TLR in RPE activation and of the interaction of TLR activated RPE with monocytic cells are given, and the potential of TLR activation in RPE as part of the AMD development is discussed. (4) Conclusion: The activation of TLR2, -3, and -4 induces a profound pro-inflammatory response in the RPE that may contribute to (long-term) inflammation by induction of pro-inflammatory cytokines, reducing RPE function and causing RPE cell degeneration, thereby potentially constantly providing new TLR ligands, which could perpetuate and, in the long run, exacerbate the inflammatory response, which may contribute to AMD development. Furthermore, the combined activation of RPE and microglia may exacerbate neurotoxic effects.

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A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

Nutrients ◽

10.3390/nu13072441 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2441

Author(s):

Drake W. Lem ◽

Dennis L. Gierhart ◽

Pinakin Gunvant Davey

Keyword(s):

Diabetic Retinopathy ◽

Vision Loss ◽

Therapeutic Potential ◽

Microvascular Disease ◽

Age Related Macular Degeneration ◽

Cell Degeneration ◽

Neuroprotective Effects ◽

Age Related ◽

Induced Changes ◽

Dietary Carotenoid

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

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Early-Onset Parkinson Disease Screening in Patients From Nigeria

Frontiers in Neurology ◽

10.3389/fneur.2020.594927 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lukasz M. Milanowski ◽

Olajumoke Oshinaike ◽

Benjamin J. Broadway ◽

Jennifer A. Lindemann ◽

Alexandra I. Soto-Beasley ◽

...

Keyword(s):

Functional Analysis ◽

Parkinson Disease ◽

Neurodegenerative Diseases ◽

Early Onset ◽

Local Population ◽

Age At Onset ◽

Compound Heterozygous ◽

Loss Of Function ◽

African Countries ◽

Age Related

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

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Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

Visual Neuroscience ◽

10.1017/s0952523805225130 ◽

2005 ◽

Vol 22 (5) ◽

pp. 637-648 ◽

Cited By ~ 208

Author(s):

RICHARD T. LIBBY ◽

MICHAEL G. ANDERSON ◽

IOK-HOU PANG ◽

ZACHARY H. ROBINSON ◽

OLGA V. SAVINOVA ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cells ◽

The Elderly ◽

Nerve Degeneration ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Future Studies ◽

Age Related ◽

Iop Elevation ◽

Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

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Age-related insult of cochlear ribbon synapses: An early-onset contributor to D-galactose-induced aging in mice

Neurochemistry International ◽

10.1016/j.neuint.2019.104649 ◽

2020 ◽

Vol 133 ◽

pp. 104649 ◽

Cited By ~ 1

Author(s):

Zheng-De Du ◽

Shu-Guang Han ◽

Teng-Fei Qu ◽

Bin Guo ◽

Shu-Kui Yu ◽

...

Keyword(s):

Early Onset ◽

Ribbon Synapses ◽

Age Related

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Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2010782117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 31278-31289

Author(s):

Sophie Boucher ◽

Fabienne Wong Jun Tai ◽

Sedigheh Delmaghani ◽

Andrea Lelli ◽

Amrit Singh-Estivalet ◽

...

Keyword(s):

Risk Factors ◽

Hearing Loss ◽

Early Onset ◽

Cell Biology ◽

Public Health Issue ◽

Phenotypic Variance ◽

Pathogenic Variants ◽

Age Related ◽

Small Effect Size ◽

Age Related Hearing Loss

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P= 0.001); half were previously unknown (AF < 0.000002).MYO6,MYO7A,PTPRQ, andTECTAvariants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also establishedTmc1N321I/+mice, carrying theTMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

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Early Onset of Age-Related Impairment of Aversive and Appetitive Learning in the SAM-P/8 Mouse

Journal of Gerontology ◽

10.1093/geronj/47.2.b52 ◽

1992 ◽

Vol 47 (2) ◽

pp. B52-B59 ◽

Cited By ~ 80

Author(s):

J. F. Flood ◽

J. E. Morley

Keyword(s):

Early Onset ◽

Appetitive Learning ◽

Age Related

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Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements

Brain Imaging and Behavior ◽

10.1007/s11682-010-9101-4 ◽

2010 ◽

Vol 4 (3-4) ◽

pp. 220-231 ◽

Cited By ~ 23

Author(s):

Melissa Lopez-Larson ◽

Janis L. Breeze ◽

David N. Kennedy ◽

Steven M. Hodge ◽

Lena Tang ◽

...

Keyword(s):

Bipolar Disorder ◽

Corpus Callosum ◽

Early Onset ◽

Cross Sectional ◽

Age Related ◽

Age Related Changes

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The Effect of Cochleostomy on the Development of Endolymphatic Hydrops—Morphologic Changes in the Rabbit Cochlea

Otolaryngology ◽

10.1177/019459988809800402 ◽

1988 ◽

Vol 98 (4) ◽

pp. 283-290 ◽

Cited By ~ 3

Author(s):

E. A. Dimitrov ◽

L. G. Duckert ◽

B. L. Lonsbury-Martin ◽

G. K. Martin

Keyword(s):

Electron Microscope ◽

Scanning Electron Microscope ◽

Sensory Cell ◽

Endolymphatic Hydrops ◽

Cell Damage ◽

Cell Degeneration ◽

Duct Obstruction ◽

Endolymphatic Duct ◽

Cochlear Partition ◽

Scanning Electron

The present study was designed to examine the effects of cochieostomy on the development of endolymphatic hydrops in the rabbit. Fistulization of the cochlear partition and simultaneous obstruction of the endolymphatic duct was performed in one group of animals ( n = 13). Rabbits in two other groups underwent either cochleostomy (n = 6) or endolymphatic duct obstruction (n = 6) alone. Animals were terminated at 1-, 4-, and 6-week Intervals and the cochleas were examined with the light microscope to document the presence or absence of hydrops, or were evaluated with the scanning electron microscope to assess sensory-cell damage. Hydrops was observed In 67% of the animals In the combined duct-obstruction/cochleostomy group, In 100% of the duct-obstruction alone group, and In 0% of the cochleostomy alone group. Widespread sensory-cell degeneration was observed with the scanning electron microscope in the combined and the cochleostomy alone groups.

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