scholarly journals α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

2021 ◽  
Vol 22 (21) ◽  
pp. 11339
Author(s):  
Ulrich Jehn ◽  
Samet Bayraktar ◽  
Solvey Pollmann ◽  
Veerle Van Marck ◽  
Thomas Weide ◽  
...  
Keyword(s):  
Protein Expression ◽  
Fabry Disease ◽  
Neurological Diseases ◽  
Proteome Analysis ◽  
Cell Types ◽  
Patient Specific ◽  
Loss Of Function ◽  
Cardiovascular Morbidity And Mortality ◽  
Cellular Pathways ◽  
And Function

Fabry disease (FD) is caused by mutations in the α-galactosidase A (GLA) gene encoding the lysosomal AGAL enzyme. Loss of enzymatic AGAL activity and cellular accumulation of sphingolipids (mainly globotriaosylcermide) may lead to podocyturia and renal loss of function with increased cardiovascular morbidity and mortality in affected patients. To identify dysregulated cellular pathways in FD, we established a stable AGAL-deficient podocyte cell line to perform a comprehensive proteome analysis. Imbalanced protein expression and function were analyzed in additional FD cell lines including endothelial, epithelial kidney, patient-derived urinary cells and kidney biopsies. AGAL-deficient podocytes showed dysregulated proteins involved in thermogenesis, lysosomal trafficking and function, metabolic activity, cell-cell interactions and cell cycle. Proteins associated with neurological diseases were upregulated in AGAL-deficient podocytes. Rescues with inducible AGAL expression only partially normalized protein expression. A disturbed protein expression was confirmed in endothelial, epithelial and patient-specific cells, pointing toward fundamental pathway disturbances rather than to cell type-specific alterations in FD. We conclude that a loss of AGAL function results in profound changes of cellular pathways, which are ubiquitously in different cell types. Due to these profound alterations, current approved FD-specific therapies may not be sufficient to completely reverse all dysregulated pathways.

scholarly journals Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2371-2380 ◽  
Author(s):  
Benjamin T. Kile ◽  
Athanasia D. Panopoulos ◽  
Roslynn A. Stirzaker ◽  
Douglas F. Hacking ◽  
Lubna H. Tahtamouni ◽  
...  
Keyword(s):  
Autoinflammatory Disease ◽  
Cell Types ◽  
Actin Dynamics ◽  
Loss Of Function ◽  
Allelic Series ◽  
Interacting Protein ◽  
Normal Platelet ◽  
Cytoskeletal Responses ◽  
Hypomorphic Alleles ◽  
And Function

A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow–derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.

scholarly journals Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex.

1994 ◽  
Vol 127 (3) ◽  
pp. 707-723 ◽  
Author(s):  
K A Beck ◽  
J A Buchanan ◽  
V Malhotra ◽  
W J Nelson
Keyword(s):  
Golgi Complex ◽  
Structural Integrity ◽  
Functional Organization ◽  
Brefeldin A ◽  
Cell Types ◽  
Loss Of Function ◽  
Dynamic Relationship ◽  
Golgi Membranes ◽  
Golgi Structure ◽  
And Function

Spectrin is a major component of a membrane-associated cytoskeleton involved in the maintenance of membrane structural integrity and the generation of functionally distinct membrane protein domains. Here, we show that a homolog of erythrocyte beta-spectrin (beta I sigma*) co-localizes with markers of the Golgi complex in a variety of cell types, and that microinjected beta-spectrin codistributes with elements of the Golgi complex. Significantly, we show a dynamic relationship between beta-spectrin and the structural and functional organization of the Golgi complex. Disruption of both Golgi structure and function, either in mitotic cells or following addition of brefeldin A, is accompanied by loss of beta-spectrin from Golgi membranes and dispersal in the cytoplasm. In contrast, perturbation of Golgi structure without a loss of function, by the addition of nocodazole, results in retention of beta-spectrin with the dispersed Golgi elements. These results indicate that the association of beta-spectrin with Golgi membranes is coupled to Golgi organization and function.

scholarly journals Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function

2021 ◽  
Author(s):  
Alanna G. Spiteri ◽  
Claire L. Wishart ◽  
Roger Pamphlett ◽  
Giuseppe Locatelli ◽  
Nicholas J. C. King
Keyword(s):  
Viral Encephalitis ◽  
Neurological Diseases ◽  
Cell Types ◽  
Cell Type ◽  
Neuroinflammatory Disease ◽  
Experimental Systems ◽  
Immune Mediated ◽  
Experimental Approaches ◽  
And Function ◽  
Disease Specific

AbstractIn neurological diseases, the actions of microglia, the resident myeloid cells of the CNS parenchyma, may diverge from, or intersect with, those of recruited monocytes to drive immune-mediated pathology. However, defining the precise roles of each cell type has historically been impeded by the lack of discriminating markers and experimental systems capable of accurately identifying them. Our ability to distinguish microglia from monocytes in neuroinflammation has advanced with single-cell technologies, new markers and drugs that identify and deplete them, respectively. Nevertheless, the focus of individual studies on particular cell types, diseases or experimental approaches has limited our ability to connect phenotype and function more widely and across diverse CNS pathologies. Here, we critically review, tabulate and integrate the disease-specific functions and immune profiles of microglia and monocytes to provide a comprehensive atlas of myeloid responses in viral encephalitis, demyelination, neurodegeneration and ischemic injury. In emphasizing the differential roles of microglia and monocytes in the severe neuroinflammatory disease of viral encephalitis, we connect inflammatory pathways common to equally incapacitating diseases with less severe inflammation. We examine these findings in the context of human studies and highlight the benefits and inherent limitations of animal models that may impede or facilitate clinical translation. This enables us to highlight common and contrasting, non-redundant and often opposing roles of microglia and monocytes in disease that could be targeted therapeutically.

scholarly journals ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 408 ◽  
Author(s):  
Bo Wang ◽  
Katherine R. Stanford ◽  
Mondira Kundu
Keyword(s):  
Protein Localization ◽  
Neurological Diseases ◽  
Cell Types ◽  
Cellular Function ◽  
Secretory Protein ◽  
Secretory Proteins ◽  
Complex Cell ◽  
Final Destination ◽  
And Function ◽  
Spatiotemporal Control

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans.

scholarly journals PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Miguel Hernandez-Quiles ◽  
Marjoleine F. Broekema ◽  
Eric Kalkhoven
Keyword(s):  
Regulatory Networks ◽  
Target Gene ◽  
Critical Role ◽  
Tumor Development ◽  
Cell Types ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Treatment Of Obesity ◽  
And Function ◽  
Cancer And Inflammation

The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation—where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα—is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression—where PPARγ alters gene expression independent of DNA binding—is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ’s target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.

scholarly journals Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
James M Mossner ◽  
Renata Batista-Brito ◽  
Rima Pant ◽  
Jessica A Cardin
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Cell Types ◽  
Loss Of Function ◽  
Cortical Function ◽  
Behavioral Phenotypes ◽  
Pathophysiological Role ◽  
And Function ◽  
And Behavior

Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.

scholarly journals Altered ER–mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models

2018 ◽  
Vol 115 (38) ◽  
pp. E8844-E8853 ◽  
Author(s):  
Kyu-Sun Lee ◽  
Sungun Huh ◽  
Seongsoo Lee ◽  
Zhihao Wu ◽  
Ae-Kyeong Kim ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Independent Manner ◽  
Lrrk2 G2019s ◽  
Mutant Phenotypes ◽  
Cellular Compartments

Calcium (Ca2+) homeostasis is essential for neuronal function and survival. Altered Ca2+ homeostasis has been consistently observed in neurological diseases. How Ca2+ homeostasis is achieved in various cellular compartments of disease-relevant cell types is not well understood. Here we show in Drosophila Parkinson’s disease (PD) models that Ca2+ transport from the endoplasmic reticulum (ER) to mitochondria through the ER–mitochondria contact site (ERMCS) critically regulates mitochondrial Ca2+ (mito-Ca2+) homeostasis in dopaminergic (DA) neurons, and that the PD-associated PINK1 protein modulates this process. In PINK1 mutant DA neurons, the ERMCS is strengthened and mito-Ca2+ level is elevated, resulting in mitochondrial enlargement and neuronal death. Miro, a well-characterized component of the mitochondrial trafficking machinery, mediates the effects of PINK1 on mito-Ca2+ and mitochondrial morphology, apparently in a transport-independent manner. Miro overexpression mimics PINK1 loss-of-function effect, whereas inhibition of Miro or components of the ERMCS, or pharmacological modulation of ERMCS function, rescued PINK1 mutant phenotypes. Mito-Ca2+ homeostasis is also altered in the LRRK2-G2019S model of PD and the PAR-1/MARK model of neurodegeneration, and genetic or pharmacological restoration of mito-Ca2+ level is beneficial in these models. Our results highlight the importance of mito-Ca2+ homeostasis maintained by Miro and the ERMCS to mitochondrial physiology and neuronal integrity. Targeting this mito-Ca2+ homeostasis pathway holds promise for a therapeutic strategy for neurodegenerative diseases.

scholarly journals Human SYNGAP1 Regulates the Development of Neuronal Activity by Controlling Dendritic and Synaptic Maturation

2020 ◽  
Author(s):  
Nerea Llamosas ◽  
Vineet Arora ◽  
Ridhima Vij ◽  
Murat Kilinc ◽  
Lukasz Bijoch ◽  
...  
Keyword(s):  
Protein Expression ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Global Developmental Delay ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Biological Studies ◽  
Human Neurons ◽  
And Function

AbstractSYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss-of-function impacts the development and function of human neurons. To address this, we employed CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a human induced pluripotent stem cell line (hiPSC). Reducing SynGAP protein expression in developing hiPSC-derived neurons enhanced dendritic morphogenesis, leading to larger neurons compared to those derived from isogenic controls. Consistent with larger dendritic fields, we also observed a greater number of morphologically defined excitatory synapses in cultures containing these neurons. Moreover, neurons with reduced SynGAP protein had stronger excitatory synapses and expressed synaptic activity earlier in development. Finally, distributed network spiking activity appeared earlier, was substantially elevated, and exhibited greater bursting behavior in SYNGAP1 null neurons. We conclude that SYNGAP1 regulates the postmitotic maturation of human neurons made from hiPSCs, which influences how activity develops within nascent neural networks. Alterations to this fundamental neurodevelopmental process may contribute to the etiology of SYNGAP1-related disorders.

scholarly journals β1A Integrin Is a Master Regulator of Invadosome Organization and Function

2010 ◽  
Vol 21 (23) ◽  
pp. 4108-4119 ◽  
Author(s):  
Olivier Destaing ◽  
Emmanuelle Planus ◽  
Daniel Bouvard ◽  
Christiane Oddou ◽  
Cedric Badowski ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Active Form ◽  
Focal Adhesions ◽  
Cell Types ◽  
Actin Dynamics ◽  
Loss Of Function ◽  
Protein Kinase C Activity ◽  
New Strategy ◽  
Ecm Degradation ◽  
And Function

Invadosomes are adhesion structures involved in tissue invasion that are characterized by an intense actin polymerization–depolymerization associated with β1 and β3 integrins and coupled to extracellular matrix (ECM) degradation activity. We induced the formation of invadosomes by expressing the constitutive active form of Src, SrcYF, in different cell types. Use of ECM surfaces micropatterned at the subcellular scale clearly showed that in mesenchymal cells, integrin signaling controls invadosome activity. Using β1−/− or β3−/− cells, it seemed that β1A but not β3 integrins are essential for initiation of invadosome formation. Protein kinase C activity was shown to regulate autoassembly of invadosomes into a ring-like metastructure (rosette), probably by phosphorylation of Ser785 on the β1A tail. Moreover, our study clearly showed that β1A links actin dynamics and ECM degradation in invadosomes. Finally, a new strategy based on fusion of the photosensitizer KillerRed to the β1A cytoplasmic domain allowed specific and immediate loss of function of β1A, resulting in disorganization and disassembly of invadosomes and formation of focal adhesions.

Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

1999 ◽  
Vol 81 (06) ◽  
pp. 951-956 ◽  
Author(s):  
J. Corral ◽  
R. González-Conejero ◽  
J. Rivera ◽  
F. Ortuño ◽  
P. Aparicio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cell Types ◽  
Receptor Expression ◽  
Case Control Studies ◽  
Platelet Surface ◽  
Vitro Analysis ◽  
And Function ◽  
In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

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