Proteostasis in aging-associated ocular disease

Weinberg, Jasper; Gaur, Mohita; Swaroop, Anand; Taylor, Allen

doi:10.1016/j.mam.2022.101157

Cited by 18 publications

(10 citation statements)

References 285 publications

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“…Our findings connecting mitochondrial dysfunction with oxidative stress and altered proteostasis in retinal degeneration secondary to complex I deficiency fit well within the broader context of ocular disease pathogenesis. Aberrant proteostasis has been strongly implicated in the age-related disorders macular degeneration, cataract and glaucoma [ 54 ]. Alterations in the ubiquitin/proteasome and autophagy/lysosome systems have been documented in various genetic forms of retinal degeneration and in other aging-dependent ocular diseases [ 54 , 55 ], as has oxidative stress and mitochondrial dysfunction [ 42 , 43 ], suggesting fundamental connections among these pathways.…”

Section: Discussionmentioning

confidence: 99%

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Nithianandam,

Sarkar,

Feany

2024

Human Molecular Genetics

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

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Section: Discussionmentioning

confidence: 99%

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Nithianandam,

Sarkar,

Feany

2024

Human Molecular Genetics

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“…Aberrant proteostasis has been strongly implicated in the age-related disorders macular degeneration, cataract and glaucoma (54). Alterations in the ubiquitin/proteasome and autophagy/lysosome systems have been documented in various genetic forms of retinal degeneration and in other aging-dependent ocular diseases (54,55), as has oxidative stress and mitochondrial dysfunction (42,43), suggesting fundamental connections among these pathways. A functionally important relationship between altered proteostasis and photoreceptor vulnerability was recently suggested by a chemical screening approach in an induced pluripotent stem cell-derived model of retinal degeneration caused by genetic ciliary dysfunction, which identified reserpine as both promoting photoreceptor survival and normalizing proteostasis (56).…”

Section: Discussionmentioning

confidence: 99%

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Nithianadam,

Sarkar,

Feany

2024

Preprint

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

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“…Genes with fiber cell preferred promoters in both chicken and mouse lenses were found to be enriched in GO categories mTOR signaling, Ubiquitin-mediated proteolysis, Hippo signaling, FOXO signaling, Wnt signaling, MAPK signaling, PI3K-Akt signaling, HIF-1 signaling, hypoxia, and autophagy ( Supplementary Table S2C,D ). All of these noted pathways have been functionally demonstrated to be essential for lens cell differentiation, structure, homeostasis, and/or transparency [ 1 , 7 , 155 , 156 , 157 , 158 , 159 , 160 ]. Interestingly, HIF-1 signaling was identified as an enriched signaling pathway in both epithelial cell and fiber cell genes suggesting that hypoxia-inducible transcription factor (HIF1a) plays a critical role in regulating gene expression patterns in epithelial and fiber cells during both chicken and mouse lens differentiation and could act as both an activator and a repressor of lens gene expression.…”

Section: Analysis Of Chromatin Landscape In Lens Tissues With Atac-seqmentioning

confidence: 99%

“…The 1240 evolutionarily conserved lens epithelial cell genes were submitted to the Enrichr tool [ 156 , 157 , 158 ] to identify significantly enriched cell signaling pathways and gene ontologies associated with lens epithelial cell function. Some notable enriched pathways included cell cycle, Notch signaling, hedgehog signaling, TGF-β signaling, Hippo signaling, Wnt signaling, FOXO signaling, and PI3K-Akt signaling ( Figure 7 A, Supplementary Table S4A ).…”

Section: Multiomics Integration Of Lens Differentiation Rna-seq and A...mentioning

confidence: 99%

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

et al. 2023

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Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional analysis of these genetic determinants and the pathways they regulate have provided a novel basis for the design of functional experiments to answer a wide range of long-sought biological questions. A well-characterized model for the application of these emerging technologies is the development and differentiation of the ocular lens and how individual pathways regulate lens morphogenesis, gene expression, transparency, and refraction. Recent applications of next-generation sequencing analysis on well-characterized chicken and mouse lens differentiation models using a variety of omics techniques including RNA-seq, ATAC-seq, whole-genome bisulfite sequencing (WGBS), chip-seq, and CUT&RUN have revealed a wide range of essential biological pathways and chromatin features governing lens structure and function. Multiomics integration of these data has established new gene functions and cellular processes essential for lens formation, homeostasis, and transparency including the identification of novel transcription control pathways, autophagy remodeling pathways, and signal transduction pathways, among others. This review summarizes recent omics technologies applied to the lens, methods for integrating multiomics data, and how these recent technologies have advanced our understanding ocular biology and function. The approach and analysis are relevant to identifying the features and functional requirements of more complex tissues and disease states.

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Proteostasis in aging-associated ocular disease

Cited by 18 publications

References 285 publications

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

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