Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency DOI Creative Commons

Vanitha Nithianadam,

Souvarish Sarkar, Mel Β. Feany

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 8, 2024

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number genes, including electron transport components, in large forward genetic screen for mutations causing age-related neurodegeneration context proteostasis dysfunction. created model complex I deficiency Drosophila retina to probe role protein degradation abnormalities encephalomyopathies. Using our model, we found that regulates both ubiquitin/proteasome autophagy/lysosome arms machinery. further performed an vivo kinome uncover new potentially druggable mechanisms contributing related failure. Reduction RIOK kinases innate immune signaling kinase pelle prevented animals. Genetically targeting oxidative stress, but not RIOK1 or knockdown, normalized markers. Our findings outline distinct pathways controlling introduce experimentally facile which study these debilitating currently treatment-refractory disorders.

Language: Английский

Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects DOI Creative Commons
Holly Y. Chen, Manju Swaroop, Samantha Papal

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 28, 2023

Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is major cause of incurable blindness in ciliopathies. To identify drug candidates maintain photoreceptor survival, we performed an unbiased, high-throughput screening over 6000 bioactive small molecules using organoids differentiated induced pluripotent stem cells (iPSC) rd16 mouse, which model Leber congenital amaurosis (LCA) type 10 caused by mutations the cilia-centrosomal gene CEP290 . We identified five non-toxic positive hits, including lead molecule reserpine, maintained development and survival organoids. Reserpine also improved photoreceptors derived LCA10 patients mouse retina vivo. Reserpine-treated patient revealed modulation signaling pathways related survival/death, metabolism, proteostasis. Further investigation uncovered dysregulation autophagy associated compromised primary cilium biogenesis retina. partially restored balance between ubiquitin-proteasome system at least part increasing cargo adaptor p62, resulting assembly. Our study identifies effective preclinical studies ciliopathies through cross-species discovery iPSC-derived organoids, highlights impact proteostasis pathogenesis ciliopathies, provides new insights for treatments neurodegeneration.

Language: Английский

Citations

24
Aging of the eye: Lessons from cataracts and age-related macular degeneration DOI Creative Commons
Aleš Cvekl, Jan Vijg

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 99, P. 102407 - 102407

Published: July 6, 2024

Aging is the greatest risk factor for chronic human diseases, including many eye diseases. Geroscience aims to understand effects of aging process on these genetic, molecular, and cellular mechanisms that underlie increased disease over lifetime. Understanding increases general knowledge physiology impacted by processes at various biological extremes. Two major age-related cataract macular degeneration (AMD) are caused dysfunction lens retina, respectively. Lens transparency light refraction mediated fiber cells lacking nuclei other organelles, which provides a unique opportunity study single hallmark, i.e., loss proteostasis, within an environment limited metabolism. In AMD, local photoreceptors/retinal pigmented epithelium/Bruch's membrane/choriocapillaris complex in macula leads photoreceptors eventually central vision, driven nearly all hallmarks shares features with Alzheimer's disease, Parkinson's cardiovascular diabetes. The can function as model studying basic and, vice versa, well-defined be used tools disease.

Language: Английский

Citations

14
Cysteinyl leukotriene receptor 1 modulates retinal immune cells, vascularity and proteolytic activity in aged mice DOI Creative Commons
Andreas Koller, Julia Preishuber‐Pflügl,

Daniela Mayr

et al.

Aging, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Cysteinyl leukotrienes (CysLTs) modulate the immune response, microvasculature, cell stress and endosomal-lysosomal system, are involved in cellular aging. Interestingly, CysLT receptor 1 (Cysltr1) is highly expressed retina, a tissue that strongly affected by aging process. Thus, we performed an introductory examination to determine potential importance of Cysltr1 for cells neurovascular unit using qPCR immunofluorescence analysis, on proteolytic activity retinas aged mice. Aged mice (~84 weeks) were treated orally with vehicle or 10 mg/kg montelukast (MTK), specific inhibitor, 8 weeks, 5x/week. The young (~11 served as controls. Compared control mice, exhibited increased numbers microglia reduced retinal capillary diameter, but these age-dependent changes abrogated MTK treatment. Retinal protein levels ubiquitin binding sequestosome-1 amplified aging, proteasome was decreased whereas inhibition this activity. reduction caused suppression may dampen neuroinflammation, known promoter Additionally, increase diameter after could have beneficial effect blood flow individuals. Furthermore, upon prevent accumulation toxic deposits, which hallmark tissue. Overall, promising target modulating impact

Language: Английский

Citations

1
Glycative stress as a cause of macular degeneration DOI
Eloy Bejarano, Alicia Domenech‐Bendaña,

Norma Avila-Portillo

et al.

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 101, P. 101260 - 101260

Published: March 21, 2024

Language: Английский

Citations

6
Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa DOI Open Access
Hyun Beom Song, Laura Campello, Anupam K. Mondal

et al.

Published: Jan. 21, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al. eLife 2023;12:e83205. DOI: https://doi.org/10.7554/eLife.83205). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Language: Английский

Citations

0
Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa DOI Open Access
Hyun Beom Song, Laura Campello, Anupam K. Mondal

et al.

Published: Jan. 21, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Language: Английский

Citations

0
Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single‐Cell RNA Sequencing of the Aging Mouse Retina DOI Creative Commons
Laura Campello, Matthew J. Brooks,

Benjamin R. Fadl

et al.

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 15, 2025

Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in retina, light-sensitive neuronal tissue eye where visual perception begins. Molecular mechanisms underlying retinal aging still poorly understood, highlighting need to identify biomarkers for better prognosis alleviation aging-associated vision impairment. Here, we investigate dynamics transcriptional dysregulation retina affected pathways within distinct cell types. Using an optimized protocol single-cell RNA sequencing mouse retinas at 3, 12, 18, 24 months, detect a progressive increase number differentially expressed genes across all The extent direction expression changes varies, with photoreceptor, bipolar, Müller cells showing maximum age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations rod photoreceptors bipolar cells, distributed areas retina. Our findings provide plausible molecular explanation enhanced susceptibility correlate loss scotopic sensitivity elderly individuals.

Language: Английский

Citations

0
Features That Distinguish Age-Related Macular Degeneration from Aging DOI
Dorota Skowronska‐Krawczyk, Silvia C. Finnemann, Maria B. Grant

et al.

Experimental Eye Research, Journal Year: 2025, Volume and Issue: 254, P. 110303 - 110303

Published: Feb. 20, 2025

Language: Английский

Citations

0
The Role of the Ubiquitin System in Eye Diseases DOI Creative Commons
Sandra Carolina Durán-Cristiano, Laura de Diego‐Garcia, Alba Martín‐Gil

et al.

Life, Journal Year: 2025, Volume and Issue: 15(3), P. 504 - 504

Published: March 20, 2025

The ubiquitin–proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This responsible for the degradation of proteins, while proteasomes play significant role in mechanisms involved health human diseases. participation UPS response particularly relevant, leading to involvement immunoproteasomes. specialized proteasome processing presentation antigenic peptides, making it crucial proper function. Moreover, impact considered essential understanding several diseases, such as neurodegenerative disorders, infections, vascular dysregulation may contribute pathogenesis these conditions, highlighting its importance potential therapeutic target. Interestingly, also related ocular structures, playing visual perception homeostasis. regulation processes suggests on both anterior posterior eye pathologies. review aims discuss general considerations provide information about By disease, researchers clinicians explore novel strategies targeting treatment conditions. In conclusion, player processes, with far-reaching implications segments eye. Further research this field lead development innovative therapies better complex underlying disorders.

Language: Английский

Citations

0
Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa DOI Open Access
Hyun Beom Song, Laura Campello, Anupam K. Mondal

et al.

Published: March 27, 2025

Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form IRD, is characterized by gradual dysfunction degeneration rod photoreceptors, followed loss cone photoreceptors. Recently, we identified reserpine as lead molecule for maintaining survival in mouse human organoids well rd16 mouse, which phenocopy Leber congenital amaurosis caused mutations cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, show therapeutic potential rhodopsin P23H rat model autosomal dominant RP. At postnatal day (P) 68, when males females are analyzed together, reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to controls with little or no change a-wave cone-derived photopic b-wave. Interestingly, female display enhanced a- b-waves responses at P68, along better contrast threshold increased outer nuclear layer thickness. The demonstrate preservation both photoreceptors following treatment. Retinal transcriptome analysis reveals sex-specific reserpine, significant upregulation phototransduction genes proteostasis-related pathways, notably, associated stress response. This study builds upon our previously reported results reaffirming gene-agnostic treatment IRDs emphasizes importance biological sex disease research therapy development.

Language: Английский

Citations

0