scholarly journals Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora

2021 ◽  
Author(s):  
Pasquale Pellegrini ◽  
Arnau Hervera ◽  
Olga Varea ◽  
M. Kathryn Brewer ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Tissue ◽  
Protective Mechanism ◽  
Lafora Disease ◽  
Childhood Onset ◽  
Neurological Phenotype ◽  
Associated Proteins ◽  
The Brain ◽  
Increased Susceptibility

Abstract Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

scholarly journals Lack of p62 impairs glycogen aggregation and exacerbates pathology in a mouse model of myoclonic epilepsy of Lafora

2021 ◽  
Author(s):  
Pasquale Pellegrini ◽  
Arnau Hervera Abad ◽  
Olga Varea ◽  
Mary Kathryn brewer ◽  
Iliana Lopez-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Tissue ◽  
Protective Mechanism ◽  
Lafora Disease ◽  
Childhood Onset ◽  
Neurological Phenotype ◽  
Associated Proteins ◽  
The Brain ◽  
Increased Susceptibility

Background: Lafora disease (LD) is a fatal childhood onset dementia characterized by the extensive accumulation of glycogen aggregates the so-called Lafora Bodies (LBs) in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. Methods: To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Results: Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. Conclusions: These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which to reduce the deleterious consequences of its accumulation in the brain.

scholarly journals A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256155
Author(s):  
Intakhar Ahmad ◽  
Stig Wergeland ◽  
Eystein Oveland ◽  
Lars Bø
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Corpus Callosum ◽  
Mouse Model ◽  
Grey Matter ◽  
Early Stage ◽  
Relative Proportion ◽  
Normal Appearing White Matter ◽  
The Brain

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

scholarly journals Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Anna Sintsova ◽  
Sara Smith ◽  
Sargurunathan Subashchandrabose ◽  
Harry L. Mobley
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Mouse Model ◽  
Virulence Determinants ◽  
Content Type ◽  
Immunocompromised Mouse ◽  
Common Infection ◽  
Increased Susceptibility

ABSTRACTUrinary tract infection (UTI) is the second most common infection in humans, making it a global health priority. Nearly half of all women will experience a symptomatic UTI, with uropathogenicEscherichia coli(UPEC) being the major causative agent of the infection. Although there has been extensive research on UPEC virulence determinants, the importance of host-specific metabolism remains understudied. We report here that UPEC upregulates the expression of ethanolamine utilization genes during uncomplicated UTIs in humans. We further show that UPEC ethanolamine metabolism is required for effective bladder colonization in the mouse model of ascending UTI and is dispensable for bladder colonization in an immunocompromised mouse model of UTI. We demonstrate that although ethanolamine metabolism mutants do not show increased susceptibility to antimicrobial responses of neutrophils, this metabolic pathway is important for surviving the innate immune system during UTI. This study reveals a novel aspect of UPEC metabolism in the host and provides evidence for an underappreciated link between bacterial metabolism and the host immune response.

scholarly journals The role of JAK-STAT signalling pathway promotes neurogenic-to-gliogenic shift in the brain of Ts1cje mouse model for Down syndrome

2016 ◽  
Vol 10 ◽  
Author(s):  
Lee Han-Chung ◽  
Nordin Norshariza ◽  
Vidyadaran Sharmili ◽  
Cheah Pike-See ◽  
Ling King-Hwa
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Signalling Pathway ◽  
The Brain

scholarly journals TGFβ in the obese liver mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype

2019 ◽  
Author(s):  
Antonia O. Cuff ◽  
Francesca Sillito ◽  
Simone Dertschnig ◽  
Andrew Hall ◽  
Tu Vinh Luong ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Target Cells ◽  
Alcoholic Fatty Liver ◽  
Associated Proteins ◽  
Profile Characteristic ◽  
The Cost ◽  
Increased Susceptibility

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

scholarly journals Loss of cerebellar function selectively affects intrinsic rhythmicity of eupneic breathing

2019 ◽  
Author(s):  
Yu Liu ◽  
Shuhua Qi ◽  
Fridtjof Thomas ◽  
Brittany L. Correia ◽  
Angela P. Taylor ◽  
...  
Keyword(s):  
Mouse Model ◽  
Respiratory Rate ◽  
Coefficient Of Variation ◽  
Brain Areas ◽  
Neuronal Circuitry ◽  
Cerebellar Function ◽  
Orofacial Movements ◽  
Average Coefficient ◽  
The Brain

ABSTRACTRespiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of unobstructed breathing at rest (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in the coordination of respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.

The protective mechanism of docosahexaenoic acid in mouse model of Parkinson: The role of heme oxygenase

2016 ◽  
Vol 101 ◽  
pp. 110-119 ◽  
Author(s):  
Ayse Ozkan ◽  
Hande Parlak ◽  
Gamze Tanriover ◽  
Sayra Dilmac ◽  
Seher Nasircilar Ulker ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Mouse Model ◽  
Heme Oxygenase ◽  
Protective Mechanism

scholarly journals Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes

2020 ◽  
Vol 21 (14) ◽  
pp. 5149
Author(s):  
Ching-On Wong
Keyword(s):  
Alpha Synuclein ◽  
Amyloid Precursor Proteins ◽  
Protein Species ◽  
Metabolic Fate ◽  
Cellular Toxicity ◽  
Precursor Proteins ◽  
Associated Proteins ◽  
Lysosomal System ◽  
The Brain

Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain. Internalization, intracellular trafficking, processing, and disposal of these proteins are executed by the endosomal-lysosomal system of astrocytes. Endosomal-lysosomal organelles thus mediate the cellular impact and metabolic fate of these toxic protein species. Given the indispensable role of astrocytes in brain metabolic homeostasis, the endosomal-lysosomal processing of these proteins plays a fundamental role in altering the trajectory of neurodegeneration. This review aims at summarizing the mounting evidence that has established the essential role of astrocytic endosomal-lysosomal organelles in the processing of amyloid precursor proteins, Apolipoprotein E (ApoE), tau, alpha synuclein, and huntingtin, which are associated with NDs such as Alzheimer’s, Parkinson’s, and Huntington diseases.

Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Brain ◽  
2021 ◽  
Author(s):  
Jordi Duran ◽  
Arnau Hervera ◽  
Kia H Markussen ◽  
Olga Varea ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Cell Type ◽  
Lafora Disease ◽  
Glycogen Accumulation ◽  
Lafora Bodies

Abstract The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates, called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that overaccumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

scholarly journals Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Giuseppe Galvani ◽  
Nicola Mottolese ◽  
Laura Gennaccaro ◽  
Manuela Loi ◽  
Giorgio Medici ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hippocampal Neurons ◽  
Microglial Activation ◽  
Neuronal Survival ◽  
Day Treatment ◽  
Neurodevelopmental Disorder ◽  
Stat3 Signaling ◽  
Inflammatory Status ◽  
The Brain ◽  
Increased Susceptibility

Abstract Background CDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in the CDKL5 gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD. Methods We evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression, and signaling in the brain of a mouse model of CDD, the Cdkl5 KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN, and cleaved caspase-3 immunostaining in Cdkl5 KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons of Cdkl5 KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival in Cdkl5 KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin. Results We found increased microglial activation in the brain of the Cdkl5 KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation in Cdkl5 KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus. Conclusions Our results suggest that neuroinflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients.

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