PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

Luo, Jiefeng; Huang, Xiaohua; Li, Rongjie; Xie, Jieqiong; Chen, Liechun; Zou, Chun; Zhang, Pei; Mao, Yingwei; Zou, Donghua

doi:10.1101/2022.03.11.22272061

Cited by 5 publications

(3 citation statements)

References 60 publications

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“…Meanwhile, we detected an increased expression of genes related to programmed cell death (e.g., FLCN and RASSF2 ) (Cooper et al, 2009; Schmidt and Linehan, 2018), indicating an elevated stress level in oligodendrocytes from both regions. Other examples include the microglia-specific upregulation of PTPRG , a receptor protein tyrosine phosphatase that plays a key role in mediating AD-associated neuronal death (Luo et al, 2022). In astrocytes, we observed a decreased expression of several transmembrane transporters (e.g., AQP4 and SLCO1C1 ) as well as neural transmitter metabolism enzymes (e.g., GLUD1 ), suggesting an impairment of blood-brain barrier (Silva et al, 2021) and altered metabolic state (Kulijewicz-Nawrot et al, 2013) in astrocytes from both regions of the AD brains.…”

Section: Introductionmentioning

confidence: 99%

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Sziraki

Lee

et al. 2022

Preprint

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Although several studies have applied single-cell approaches to explore gene expression changes in aged brains, they were limited by the relatively shallow sampling of brain cell populations, and thus may have failed to capture aspects of the molecular signatures and dynamics of rare cell types associated with aging and diseases. Here, we set out to investigate the age-dependent dynamics of transcription and chromatin accessibility across diverse brain cell types. With EasySci, an extensively improved single-cell combinatorial indexing strategy, we profiled ~1.5 million single-cell transcriptomes and ~400,000 single-cell chromatin accessibility profiles across mouse brains spanning different ages, genotypes, and both sexes. With a novel computational framework designed for characterizing cellular subtypes based on the expression of both genes and exons, we identified > 300 cell subtypes and deciphered the underlying molecular programs and spatial locations of rare cell types (e.g., pinealocytes, tanycytes) and subtypes. Leveraging these data, we generate a global readout of age-dependent cell population dynamics with high cellular subtype resolution, providing insights into cell types that expand (e.g., rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia and oligodendrocytes) or are depleted (e.g., neuronal progenitors, neuroblasts, committed oligodendrocyte precursors) as age progresses. Furthermore, we explored cell-type-specific responses to genetic perturbations associated with Alzheimer's disease (AD) and identify rare cell types depleted (e.g., mt-Cytb+, mt-Rnr2+ choroid plexus epithelial cells) or enriched (e.g., Col25a1+, Ndrg1+ interbrain and midbrain neurons) in both AD models. Key findings are consistent between males and females, validated across the transcriptome, chromatin accessibility, and spatial analyses. Finally, we profiled a total of 118,240 single-nuclei transcriptomes from twenty-four human brain samples derived from control and AD patients, revealing highly cell-type-specific and region-specific gene expression changes associated with AD pathogenesis. Critical AD-associated gene signatures were validated in both human and mice. In summary, these data comprise a rich resource for exploring cell-type-specific dynamics and the underlying molecular mechanisms in both normal and pathological mammalian aging.

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Section: Introductionmentioning

confidence: 99%

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Sziraki

Lee

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Highlighting the role of microglia in the disease, we observed that PTPRG , a protein tyrosine phosphatase receptor, is upregulated in AD and stands out substantially from all other genes in terms of effect size and p-value. PTPRG is an inflammatory marker but its role in the molecular etiology of AD is unclear 43 , 44 . Interestingly, PTPRG is among the three genes (the other two being APOE and DYPD ) that are reliably upregulated in two out of three previous human microglia transcriptome studies 45 .…”

Section: Discussionmentioning

confidence: 99%

Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Hoffman

Lee

Bendl

et al. 2023

Preprint

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Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models to identify genes differentially expressed with traits across subjects for each cell cluster. Designed for data from large cohorts, dreamlet is substantially faster and uses less memory than existing workflows, while supporting complex statistical models and controlling the false positive rate. We demonstrate computational and statistical performance on published datasets, and a novel dataset of 1.4M single nuclei from postmortem brains of 150 Alzheimer’s disease cases and 149 controls.

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“…Many of the LR pairs unique to ARM involved neuroprotective and glioprotective factors, such as APOE-SORL1 [58], CD47-SIRPA [59], and PSAP-GPR37L1 [60]) (Supplementary Figure S10). In contrast, disease-enriched LR pairs involving pathology-associated microglia included mediators of cellular damage, including complement (C3-CD46) [61], cholesterol scavenger receptors (PTDSS1-SCARB1) [62], and drivers of microglia-mediated neuronal death (CNTN4-PTPRG) [63] (Supplementary Figure S11). Other LR pairs were shared by both types of disease-associated microglia such as interactions involving the AD disease gene APOE with LRP5, but these were different from those with homeostatic or dystrophic microglia (Supplementary Figures S12 and S13; Supplementary Tables S8-S10).…”

Section: Multinichenet Reveals Markedly Increased CCI Involving Deple...mentioning

confidence: 99%

Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer’s Disease

Yamakawa,

Rexach

2024

Biomedicines

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Alzheimer’s disease (AD) is a multi-stage neurodegenerative disorder characterized by beta-amyloid accumulation, hyperphosphorylated Tau deposits, neurodegeneration, neuroinflammation, and cognitive impairment. Recent studies implicate CD8 T cells as neuroimmune responders to the accumulation of AD pathology in the brain and potential contributors to toxic neuroinflammation. However, more evidence is needed to understand lymphocytes in disease, including their functional states, molecular mediators, and interacting cell types in diseased brain tissue. The scarcity of lymphocytes in brain tissue samples has limited the unbiased profiling of disease-associated cell types, cell states, drug targets, and relationships to common AD genetic risk variants based on transcriptomic analyses. However, using recent large-scale, high-quality single-nuclear sequencing datasets from over 84 Alzheimer’s disease and control cases, we leverage single-nuclear RNAseq data from 800 lymphocytes collected from 70 individuals to complete unbiased molecular profiling. We demonstrate that effector memory CD8 T cells are the major lymphocyte subclass enriched in the brain tissues of individuals with AD dementia. We define disease-enriched interactions involving CD8 T cells and multiple brain cell subclasses including two distinct microglial disease states that correlate, respectively, to beta-amyloid and tau pathology. We find that beta-amyloid-associated microglia are a major hub of multicellular cross-talk gained in disease, including interactions involving both vulnerable neuronal subtypes and CD8 T cells. We reproduce prior reports that amyloid-response microglia are depleted in APOE4 carriers. Overall, these human-based studies provide additional support for the potential relevance of effector memory CD8 T cells as a lymphocyte population of interest in AD dementia and provide new candidate interacting partners and drug targets for further functional study.

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PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

Cited by 5 publications

References 60 publications

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer’s Disease

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