Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

Shinozaki, Youichi; Leung, Alex; Namekata, Kazuhiko; Saitoh, Shu‐ichi; Nguyen, Huy Bang; Takeda, Akiko; Danjo, Yosuke; Morizawa, Yosuke; Shigetomi, Eiji; Sano, Fumikazu; Yoshioka, Nozomu; Takebayashi, Hirohide; Ohno, Nobuhiko; Segawa, Tomio; Miyake, Kunio; Kashiwagi, Kenji; Harada, Takayuki; Ohnuma, Shin-ichi; Koizumi, Schuichi

doi:10.1126/sciadv.abq1081

Cited by 19 publications

(11 citation statements)

References 73 publications

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“…C57BL/6 mice are nearly genetically identical with only ∼15,000 SNPs and insertion–deletion mutations (indels) ( Doran et al, 2016 ), providing evidence that SNP-based demuxers are unable to separate biological replicates from highly inbred mice. We also attempted SNP-based demultiplexing of in silico–pooled data from DBA/1J mice ( Shinozaki et al, 2022 ) which have ∼5 × 10 6 total SNPs and indels ( Doran et al, 2016 ). Again, 99.7% of cells were unable to be assigned via souporcell (data not shown), suggesting that SNP-based demultiplexing is incompatible with highly inbred animals.…”

Section: Resultsmentioning

confidence: 99%

“…C57BL/6 data were downloaded from SRR15502048 , SRR15502052 , and SRR15502056 ( Crowl et al, 2022 ). For DBA data ( Shinozaki et al, 2022 ) possorted.bam files were downloaded from SRA. wget https://sra-pub-src-1.s3.amazonaws.com/SRR20079758/WT3_possorted_genome_bam.bam.1 wget https://sra-pub-src-1.s3.amazonaws.com/SRR20079759/WT2_possorted_genome_bam.bam.1 wget https://sra-pub-src-2.s3.amazonaws.com/SRR20079760/WT1_possorted_genome_bam.bam.1 .…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of genetic demultiplexing of single-cell sequencing data from model species

et al. 2023

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Single-cell sequencing (sc-seq) provides a species agnostic tool to study cellular processes. However, these technologies are expensive and require sufficient cell quantities and biological replicates to avoid artifactual results. An option to address these problems is pooling cells from multiple individuals into one sc-seq library. In humans, genotype-based computational separation (i.e., demultiplexing) of pooled sc-seq samples is common. This approach would be instrumental for studying non-isogenic model organisms. We set out to determine whether genotype-based demultiplexing could be more broadly applied among species ranging from zebrafish to non-human primates. Using such non-isogenic species, we benchmark genotype-based demultiplexing of pooled sc-seq datasets against various ground truths. We demonstrate that genotype-based demultiplexing of pooled sc-seq samples can be used with confidence in several non-isogenic model organisms and uncover limitations of this method. Importantly, the only genomic resource required for this approach is sc-seq data and a de novo transcriptome. The incorporation of pooling into sc-seq study designs will decrease cost while simultaneously increasing the reproducibility and experimental options in non-isogenic model organisms.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Evaluation of genetic demultiplexing of single-cell sequencing data from model species

et al. 2023

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“…This vicious cycle between tau hyperphosphorylation and oxidative stress [113], as well as tau aggregate formation, can induce glial inflammation (astrogliosis) and neuropathology in Alzheimer's disease-related mouse models via innate immune sensors (receptors) such as Tool-like receptors (TLRs) [119]. In fact, tau-containing astrocytes have been discovered in numerous tauopathies, including glaucoma [120,121].…”

Section: Oxidative Damage Is a Common Feature In Both Glaucoma And Ta...mentioning

confidence: 99%

Glaucoma as a Tauopathy—Is It the Missing Piece in the Glaucoma Puzzle?

Passaro,

Matarazzo,

Abbadessa

et al. 2023

JCM

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Glaucoma is a chronic neurodegenerative disorder affecting the visual system which can result in vision loss and blindness. The pathogenetic mechanisms underlying glaucomatous optic neuropathy are ultimately enigmatic, prompting ongoing investigations into its potential shared pathogenesis with other neurodegenerative neurological disorders. Tauopathies represent a subclass of neurodegenerative diseases characterized by the abnormal deposition of tau protein within the brain and consequent microtubule destabilization. The extended spectrum of tauopathies includes conditions such as frontotemporal dementias, progressive supranuclear palsy, chronic traumatic encephalopathy, and Alzheimer’s disease. Notably, recent decades have witnessed emerging documentation of tau inclusion among glaucoma patients, providing substantiation that this ocular disease may similarly manifest features of tauopathies. These studies found that: (i) aggregated tau inclusions are present in the somatodendritic compartment of RGCs in glaucoma patients; (ii) the etiology of the disease may affect tau splicing, phosphorylation, oligomerization, and subcellular localization; and (iii) short interfering RNA against tau, administered intraocularly, significantly decreased retinal tau accumulation and enhanced RGC somas and axon survival, demonstrating a crucial role for tau modifications in ocular hypertension-induced neuronal injury. Here, we examine the most recent evidence surrounding the interplay between tau protein dysregulation and glaucomatous neurodegeneration. We explore the novel perspective of glaucoma as a tau-associated disorder and open avenues for cross-disciplinary collaboration and new treatment strategies.

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“…In another example, inspired by the relationship between aging and glaucoma in clinical settings, Lu et al designed retinal tissue reprogramming through the induction of ectopic expression of the four Yamanaka transcription factors and showed reverse age-related vision loss and eye damage in an aging mouse model with glaucoma (6). These and other related studies demonstrated the successful implication of reverse translation in glaucoma research (7)(8)(9).…”

Section: Introduction 1reverse Translation In Glaucoma Studiesmentioning

confidence: 99%

Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications

Pasquale

Girard

et al. 2023

Front. Ophthalmol.

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Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data.

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Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

Cited by 19 publications

References 73 publications

Evaluation of genetic demultiplexing of single-cell sequencing data from model species

Evaluation of genetic demultiplexing of single-cell sequencing data from model species

Glaucoma as a Tauopathy—Is It the Missing Piece in the Glaucoma Puzzle?

Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications

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