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    Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease
    (2022)
    Sandra Espinoza
    ;
    Felipe Grunenwald
    ;
    Wileidy Gomez
    ;
    Felipe García
    ;
    Lorena Abarzúa-Catalan  
    <jats:p>Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.</jats:p>
    Scopus© Citations 2  5
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    Brain’s Energy After Stroke: From a Cellular Perspective Toward Behavior
    (2022)
    Juan José Mariman
    ;
    Enrique Lorca
    ;
    Carlo Biancardi
    ;
    Pablo Burgos
    ;
    Joel Álvarez-Ruf
    <jats:p>Stroke is a neurological condition that impacts activity performance and quality of life for survivors. While neurological impairments after the event explain the performance of patients in specific activities, the origin of such impairments has traditionally been explained as a consequence of structural and functional damage to the nervous system. However, there are important mechanisms related to energy efficiency (trade-off between biological functions and energy consumption) at different levels that can be related to these impairments and restrictions: first, at the neuronal level, where the availability of energy resources is the initial cause of the event, as well as determines the possibilities of spontaneous recovery. Second, at the level of neural networks, where the “small world” operation of the network is compromised after the stroke, implicating a high energetic cost and inefficiency in the information transfer, which is related to the neurological recovery and clinical status. Finally, at the behavioral level, the performance limitations are related to the highest cost of energy or augmented energy expenditure during the tasks to maintain the stability of the segment, system, body, and finally, the behavior of the patients. In other words, the postural homeostasis. In this way, we intend to provide a synthetic vision of the energy impact of stroke, from the particularities of the operation of the nervous system, its implications, as one of the determinant factors in the possibilities of neurological, functional, and behavioral recovery of our patients.</jats:p>
    Scopus© Citations 2  1
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    Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis
    (2022)
    Mariela Puebla
    ;
    Pablo J. Tapia
    ;
    Hilda Espinoza
    <jats:p>Angiogenesis is a key process in various physiological and pathological conditions in the nervous system and in the retina during postnatal life. Although an increasing number of studies have addressed the role of endothelial cells in this event, the astrocytes contribution in angiogenesis has received less attention. This review is focused on the role of astrocytes as a scaffold and in the stabilization of the new blood vessels, through different molecules release, which can modulate the angiogenesis process in the brain and in the retina. Further, differences in the astrocytes phenotype are addressed in glioblastoma, one of the most devastating types of brain cancer, in order to provide potential targets involved in the cross signaling between endothelial cells, astrocytes and glioma cells, that mediate tumor progression and pathological angiogenesis. Given the relevance of astrocytes in angiogenesis in physiological and pathological conditions, future studies are required to better understand the interrelation between endothelial and astrocyte signaling pathways during this process.</jats:p>
      2Scopus© Citations 39
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    Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
    (2022)
    Sophia Davidson
    ;
    Chien-Hsiung Yu
    ;
    Annemarie Steiner
    ;
    Frédéric Ebstein
    ;
    Paul J. Baker
    <jats:p>Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.</jats:p>
    Scopus© Citations 55  3
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    Scopus© Citations 10  1
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    Scopus© Citations 2  1
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      11Scopus© Citations 71
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      11
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      1Scopus© Citations 142