Mir-284-dependent dynamics of the Drosophila antennal transcriptome during aging
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE103910 | GEO | 2020/09/15
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
2011-12-23 | E-GEOD-25009 | biostudies-arrayexpress
Project description:1. Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon–myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages—important representatives of the innate immune system—are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses. Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function. 2. Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant oligodendrocyte myelin. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
2021-02-08 | GSE138891 | GEO
Project description:Adult stem cells undergo functional degeneration during aging. Quercetin exhibits many beneficial effects against aging and aging-related diseases. Using Drosophila as a model, we explore the efficacy of quercetin against adult stem cell aging and provide effective and feasible therapeutic solutions for preventing the aging-related functional decline of stem cells.
2022-12-06 | GSE216546 | GEO
Project description:Aging is a prominent risk factor for neurodegenerative disease, therefore defining mechanisms critical for healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such genes, we have pursued analysis of miR-34 mutants in Drosophila. The miR-34 mutant brain displays a gene profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We investigated targets of miR-34 to define those important for its functions in mitigating degeneration and impacting health of the brain with age. These studies show that miR-34 targets for silencing two components of polycomb repressive complex 2 (PRC2)—Pcl and Su(z)12—in the brain with age. PRC2 is a histone methyltransferase that confers the repressive H3K27me3 mark, suggesting that a critical role of miR-34 is to modulate the function of PRC2 to silence key genes in the brain with age. Remarkably, gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key modulated genes. These findings indicate that PRC2 epigenetic mechanisms impact the susceptibility of the brain to degenerative disease with age, and highlight the role of small heat shock proteins to protect the brain from age-associated decline and disease.
2018-10-10 | GSE110135 | GEO
Project description:Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by microcirculatory and diastolic dysfunction and increased susceptibility to arrhythmias. Nerves align with vessels during development. However, the impact of aging on the cardiac neuro-vascular interface is entirely unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion, which increased Sema3a expression, or endothelial Sema3a overexpression reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reduced Sema3a expression, preserved heart rate variability and reduced electrical instability. These data suggest that senescence-associated regulation of neuro-regulatory genes is associated with reduced nerve density and, thereby, contributes to age-associated cardiac dysfunction.
2023-07-05 | E-MTAB-13093 | biostudies-arrayexpress
Project description:Cytotoxic CNS-associated T cells drive axon degeneration in aging and myelin disease
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Project description:Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remains elusive. Here, we show that microRNAs are differentially expressed during RGC development, and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of PTEN, a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and increases axon extension in RGCs isolated from aged human donors. This uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity via intravitreal injection in patients with optic neuropathies.
2020-07-04 | GSE102458 | GEO
Project description:The enormous cellular diversity and complex tissue organization of the brain have hindered systematic characterization of its age-related changes in cellular and molecular architecture and mechanistic understanding of its functional decline and degeneration during aging. Here we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified the changes in gene expression and spatial organization of major cell types in these regions over the lifespan of mice. We observed more pronounced changes in the composition, gene expression and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly within the white matter of the corpus callosum, and identified both similarities and differences in cell activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain.
2022-07-13 | GSE207848 | GEO
Project description:Adult aging is a complex biological process associated with altered gene expression and a decline in physiological performance. The microRNAs have been implicated in cardiac development, cardiac hypertrophy and heart failure. However, the impact of adult aging on cardiac expression of both miRNA guide strand (miR) and passenger strand (miR*), as well as miRNA clusters have not been well established. We explored the expression profile of both miR and miR* in the heart. We found that 65 miRNAs were differentially expressed in old versus young adult heart; approximately half of them were clustered miRNAs that were distributed in 11 miRNA clusters. Each miRNA cluster contains from 2 to as many as 71 miRNA genes. The majority of the clusters displayed unified expression, with most cluster members within a cluster being either increased or decreased together, suggesting that most clusters are regulated by a common signaling mechanism and that the combined expression of multiple miRNA genes in a cluster could pose an impact on a broad range of targets during aging. We also found age-related changes in the expression of miR*s. Bioinformatic analysis revealed that miR-21 and miR-21* had their own silencing targets. The expression of both miR and miR* correlated with that of pri-miRNA transcript over the time course from development and maturation through adult aging. Age-related changes in the expression of Ago1 and Ago2 proteins in the heart were also observed. Our data suggest that a concert of effects, including transcriptional regulation of pri-miRNA transcript and altered expression of Argonaut proteins, contribute to age-related changes in the expression of both miR and miR* strands during adult aging. The major changes occurred later in life, from middle to old age. It is likely that the expression of both miR and miR* is regulated by transcription and Ago1 and Ago2 proteins. Six healthy C57BL/6 mice were used in this study. Three of them were 4 months old (young adult mice: YA), and the other three were 24 months old (old mice). Total RNA samples were isolated from mouse hearts and then shipped to Exiqon Inc., where microRNA array analysis was performed. Three array slides were used for the hybridization. Each array slide hybridized with two samples labeld with either Hy3 or Hy5, with array #1 being hybridized with samples YA-1 (Hy3) and Old-1 (Hy5), array #2 with samples YA-2 (Hy3) and Old-2 (Hy5) and array #3 with samples YA-3 (Hy5) and Old-3 (Hy3). In our publication, we reveal the detail of the experiment and statistical analysis that were provided by Exiqon Inc.
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