scholarly journals Loss of Wwox Causes Defective Development of Cerebral Cortex with Hypomyelination in a Rat Model of Lethal Dwarfism with Epilepsy

2019 ◽  
Vol 20 (14) ◽  
pp. 3596 ◽  
Author(s):  
Yuki Tochigi ◽  
Yutaka Takamatsu ◽  
Jun Nakane ◽  
Rika Nakai ◽  
Kentaro Katayama ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Rat Model ◽  
Physiological Role ◽  
Early Death ◽  
Neurite Growth ◽  
Loss Of Function ◽  
Age Related ◽  
Putative Tumor Suppressor ◽  
Severe Reduction

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.

The role of PCSK9 in infectious diseases.

2021 ◽  
Vol 28 ◽  
Author(s):  
Laura Magnasco ◽  
Chiara Sepulcri ◽  
Roberta Maria Antonello ◽  
Stefano Di Bella ◽  
Laura Labate ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Malaria Infection ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Physiological Role ◽  
Protective Role ◽  
Loss Of Function ◽  
Pcsk9 Inhibition ◽  
Sepsis And Septic Shock

Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, particularly regarding its role in lipid metabolism, cardiovascular risk, and its role in innate immunity. Increasing evidence is available about the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, and the regulation of host response to bacterial infections, primarily sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: This paper aims to review the available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients to treat HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Finally, a loss of function in the PCSK9-encoding gene has been reported to reduce malaria infection mortality.

scholarly journals Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth

2009 ◽  
Vol 284 (24) ◽  
pp. 16482-16491 ◽  
Author(s):  
Julia Sämann ◽  
Jan Hegermann ◽  
Erika von Gromoff ◽  
Stefan Eimer ◽  
Ralf Baumeister ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Parkinson Disease ◽  
Neurite Outgrowth ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
C Elegans ◽  
Genes Encoding

Mutations in two genes encoding the putative kinases LRRK2 and PINK1 have been associated with inherited variants of Parkinson disease. The physiological role of both proteins is not known at present, but studies in model organisms have linked their mutants to distinct aspects of mitochondrial dysfunction, increased vulnerability to oxidative and endoplasmic reticulum stress, and intracellular protein sorting. Here, we show that a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons. We demonstrate that in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-of-function mutants were suppressed. Conversely, the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background. These results provide the first evidence of an antagonistic role of PINK-1 and LRK-1. Due to the similarity of the C. elegans proteins to human LRRK2 and PINK1, we suggest a common role of both factors in cellular functions including stress response and regulation of neurite outgrowth. This study might help to link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes resulting from Parkinson disease-related mutants in both genes, the first manifestations of which are cytoskeletal defects in affected neurons.

Guwiyang Wurra–‘Fire Mouse’: a global gene knockout model for TSPO/PBR drug development, loss-of-function and mechanisms of compensation studies

2015 ◽  
Vol 43 (4) ◽  
pp. 553-558 ◽  
Author(s):  
Ryan J. Middleton ◽  
Guo-Jun Liu ◽  
Richard B. Banati
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Gene Knockout ◽  
Physiological Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Benzodiazepine Receptor ◽  
Translocator Protein ◽  
Loss Of Function ◽  
Recent Developments

The highly conserved 18-kDa translocator protein (TSPO) or peripheral benzodiazepine receptor (PBR), is being investigated as a diagnostic and therapeutic target for disease conditions ranging from inflammation to neurodegeneration and behavioural illnesses. Many functions have been attributed to TSPO/PBR including a role in the mitochondrial permeability transition pore (MPTP), steroidogenesis and energy metabolism. In this review, we detail the recent developments in determining the physiological role of TSPO/PBR, specifically based on data obtained from the recently generated Tspo knockout mouse models. In addition to defining the role of TSPO/PBR, we also describe the value of Tspo knockout mice in determining the selectivity, specificity and presence of any off-target effects of TSPO/PBR ligands.

scholarly journals What is the physiological role of hypothalamic tanycytes in metabolism?

2021 ◽  
Author(s):  
Matei Bolborea ◽  
Fanny Langlet
Keyword(s):  
Energy Balance ◽  
Metabolic Disorders ◽  
Neural Circuits ◽  
Physiological Function ◽  
Physiological Role ◽  
Optimal Conditions ◽  
Age Related ◽  
New Research ◽  
Opening Up

In vertebrates, the energy balance process is tightly controlled by complex neural circuits that sense metabolic signals and adjust food intake and energy expenditure in line with the physiological requirements of optimal conditions. Within neural networks controlling energy balance, tanycytes are peculiar ependymoglial cells that are nowadays recognized as multifunctional players in the metabolic hypothalamus. However, the physiological function of hypothalamic tanycytes remains unclear, creating a number of ambiguities in the field. Here, we review data accumulated over the years that demonstrate the physiological function of tanycytes in the maintenance of metabolic homeostasis, opening up new research avenues. The presumed involvement of tanycytes in the pathophysiology of metabolic disorders and age-related neurodegenerative diseases will be finally discussed.

scholarly journals The age-regulated zinc finger factor ZNF367 is a new modulator of embryonic neurogenesis

2018 ◽  
Author(s):  
Valentina Naef ◽  
Sara Monticelli ◽  
Debora Corsinovi ◽  
Maria Teresa Mazzetto ◽  
Alessandro Cellerino ◽  
...  
Keyword(s):  
Population Aging ◽  
Candidate Gene Approach ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Embryonic Neurogenesis ◽  
Age Related ◽  
The Central Nervous System ◽  
Brain Age ◽  
Global Population

AbstractGlobal population aging is one of the major social and economic challenges of contemporary society. During aging the progressive decline in physiological functions has serious consequences for all organs including brain. The age-related incidence of neurodegenerative diseases coincides with the sharp decline of the amount and functionality of adult neural stem cells. Recently, we identified a short list of brain age-regulated genes by means of next-generation sequencing. Among them znf367 codes for a transcription factor that represents a central node in gene coregulation networks during aging but its function, in the central nervous system (CNS), is completely unknown. As proof of concept we analyzed the role of znf367 during neurogenesis. By means of a gene loss of function approach limited to the CNS, we suggested that znf367 might act as a key controller of the neuroblasts cell cycle, particularly in the progression of mitosis and spindle check-point. Using a candidate gene approach, based on a weighted-gene co-expression network analysis, we suggested possible targets of znf367 such as fancd2 and ska3. The age-related decline of znf367 well correlated with its role during embryonic neurogenesis opening new lines of investigation to improved maintenance and even repair of neuronal function.

scholarly journals Visualizing endogenous opioid receptors in living neurons using ligand-directed chemistry

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Seksiri Arttamangkul ◽  
Andrew Plazek ◽  
Emily J Platt ◽  
Haihong Jin ◽  
Thomas F Murray ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Physiological Role ◽  
Loss Of Function ◽  
Wild Type ◽  
Endogenous Opioid ◽  
Covalently Linked ◽  
Living Tissues ◽  
Living Neurons ◽  
Post Hoc

Identifying neurons that have functional opioid receptors is fundamental for the understanding of the cellular, synaptic and systems actions of opioids. Current techniques are limited to post hoc analyses of fixed tissues. Here we developed a fluorescent probe, naltrexamine-acylimidazole (NAI), to label opioid receptors based on a chemical approach termed ‘traceless affinity labeling’. In this approach, a high affinity antagonist naltrexamine is used as the guide molecule for a transferring reaction of acylimidazole at the receptor. This reaction generates a fluorescent dye covalently linked to the receptor while naltrexamine is liberated and leaves the binding site. The labeling induced by this reagent allowed visualization of opioid-sensitive neurons in rat and mouse brains without loss of function of the fluorescently labeled receptors. The ability to locate endogenous receptors in living tissues will aid considerably in establishing the distribution and physiological role of opioid receptors in the CNS of wild type animals.

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

scholarly journals Protrudin-deficient mice manifest depression-like behavior with abnormalities in activity, attention, and cued fear-conditioning

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Michiko Shirane ◽  
Hirotaka Shoji ◽  
Yutaka Hashimoto ◽  
Hiroyuki Katagiri ◽  
Shizuka Kobayashi ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Neuronal Development ◽  
Physiological Role ◽  
Loss Of Function ◽  
Reduced Body ◽  
Intermediate Phenotypes ◽  
Behavioral Abnormalities ◽  
And Behavior ◽  
Deficient Mice

Abstract Protrudin is a protein that resides in the membrane of the endoplasmic reticulum and is highly expressed in the nervous system. Although mutations in the human protrudin gene (ZFYVE27, also known as SPG33) give rise to hereditary spastic paraplegia (HSP), the physiological role of the encoded protein has been largely unclear. We therefore generated mice deficient in protrudin and subjected them to a battery of behavioral tests designed to examine their intermediate phenotypes. The protrudin-deficient mice were found to have a reduced body size and to manifest pleiotropic behavioral abnormalities, including hyperactivity, depression-like behavior, and deficits in attention and fear-conditioning memory. They exhibited no signs of HSP, however, consistent with the notion that HSP-associated mutations of protrudin may elicit neural degeneration, not as a result of a loss of function, but rather as a result of a gain of toxic function. Overall, our results suggest that protrudin might play an indispensable role in normal neuronal development and behavior.

The dual-targeted prolyl aminopeptidase PAP1 is involved in proline accumulation in response to stress and during pollen development

2021 ◽  
Author(s):  
Abi S Ghifari ◽  
Pedro F Teixeira ◽  
Beata Kmiec ◽  
Neha Singh ◽  
Elzbieta Glaser ◽  
...  
Keyword(s):  
Pollen Development ◽  
Developmental Stages ◽  
Expression Patterns ◽  
Physiological Role ◽  
Loss Of Function ◽  
Prolyl Aminopeptidase ◽  
Cellular Localisation ◽  
Alternative Transcription ◽  
Response To Stress

Abstract Plant endosymbiotic organelles such as mitochondria and chloroplasts harbour a wide array of biochemical reactions. As a part of protein homeostasis to maintain organellar activity and stability, unwanted proteins and peptides need to be completely degraded in a stepwise mechanism termed the processing pathway, where at the last stage single amino acids are released by aminopeptidases. Here, we determined the molecular and physiological functions of a prolyl aminopeptidase homologue PAP1 (At2g14260) that is able to release N-terminal proline. Transcript analyses demonstrate that an alternative transcription start site (TSS) gives rise to two alternate transcripts, generating two in-frame proteins PAP1.1 and PAP1.2. Sub-cellular localisation studies revealed that the longer isoform PAP1.1, which contains a 51-residue N-terminal extension is exclusively targeted to chloroplasts, while the truncated isoform PAP1.2 is located in the cytosol. Distinct expression patterns in different tissues and developmental stages were observed. Investigations into the physiological role of PAP1 using loss-of-function mutants revealed that PAP1 activity may be involved in proline homeostasis and accumulation, required for pollen development and tolerance to osmotic stress. Enzymatic activity, sub-cellular location, and expression patterns of PAP1 suggest a role in the chloroplastic peptide processing pathway and proline homeostasis.

scholarly journals Evaluation of the association between exosomal levels and female reproductive system and fertility outcome during aging: a systematic review protocol

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Halimeh Mobarak ◽  
Reza Rahbarghazi ◽  
Francesca Lolicato ◽  
Mohammad Heidarpour ◽  
Fariba Pashazadeh ◽  
...  
Keyword(s):  
Systematic Review ◽  
Reproductive System ◽  
Reproductive Tract ◽  
Physiological Role ◽  
Current Evidence ◽  
Gene Expressions ◽  
Younger Women ◽  
Age Related ◽  
Maternal Aging

Abstract Background Exosomes may have critical roles in the maternal-embryo cross-talk for the recognition and maintenance of pregnancy during maternal aging. Exosomes have the capability to carry developmental signaling molecules with the ability to modulate gene expressions and affect growth and regulation of embryo during pregnancy. Systematic review aims to evaluate age-related alterations in the exosomal content and functions that can influence the reproductive performance in human and animal models as conveyors of senescence signals. Methods A literature search of electronic databases including MEDLINE (PubMed), Embase, ProQuest, Scopus, Google Scholar, WHO, SID, MAGIRAN, and Barakat will be conducted. Following the online search, articles will be screened by two independent reviewers according to inclusion and exclusion criteria. Eligible studies will be critically appraised by reviewers at the study level for methodological quality using Joanna Briggs Institute’s standardized critical appraisal tools. The extracted data from selected studies will cover the study populations, methods, current evidence about the physiological role of extracellular vesicles and exosomes in reproductive system, relevant outcomes, and possible conclusions about the effectiveness of exposure. Discussion Regarding the role of exosomes and their cargoes in the function of reproductive tract, the possible beneficial or adverse effects following exosomal administration from younger women to older women will be evaluated in the systematic review. As a result, exosome therapy could be suggested as a novel therapeutic agent if the favorable results are identified.

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