bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022‒04‒24
twelve papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease.
  2. Safety and feasibility of synchronous unilateral nephrectomy and contralateral heminephrectomy for extremely severe autosomal dominant polycystic kidney disease: Techniques and outcome.
  3. Perspectives for Primary Ciliary Dyskinesia.
  4. Novel PKD2 Missense Mutation p.Ile424Ser in an Individual with Multiple Hepatic Cysts: A Case Report.
  5. 3D-Structured Illumination Microscopy of Centrosomes in Human Cell Lines.
  6. The Primary Ciliary Deficits in Cerebellar Bergmann Glia of the Mouse Model of Fragile X Syndrome.
  7. [Pathogenic genes and corresponding ciliary defects associated with primary ciliary dyskinesia].
  8. Impairment of ciliary dynamics in an APP knock-in mouse model of Alzheimer's disease.
  9. New and unexpected roles for primary cilia in coordinating response to mechanical load in articular and growth plate cartilages.
  10. Distribution of prototypical primary cilia markers in subtypes of retinal ganglion cells.
  11. Depletion of Ift88 in thymic epithelial cells affects thymic synapse and T-cell differentiation in aged mice.
  12. Microridge-like structures anchor motile cilia.
  1. Int J Mol Sci. 2022 Apr 14. pii: 4328. [Epub ahead of print]23(8):
    Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease.
    Kanlayanee Tonum, Nipitpon Srimai, Napason Chabang, Somsak Fongsupa, Patoomratana Tuchinda, Jacob A Torres, Thomas Weimbs, Sunhapas Soodvilai.
      Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5' AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague-Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD.
    Keywords:  ADPKD; AMP-activated protein kinase (AMPK); cell proliferation; cystic fibrosis transmembrane conductance regulator (CFTR); cystogenesis; renal fluid secretion
    DOI:  https://doi.org/10.3390/ijms23084328
  2. Investig Clin Urol. 2022 Apr 04.
    Safety and feasibility of synchronous unilateral nephrectomy and contralateral heminephrectomy for extremely severe autosomal dominant polycystic kidney disease: Techniques and outcome.
    Jang Hee Han, Seung-Hwan Jeong, Hyeong Dong Yuk, Ja Hyeon Ku, Cheol Kwak, Hyeon Hoe Kim, Curie Ahn, Chang Wook Jeong.
      PURPOSE: To demonstrate the safety and feasibility of synchronous unilateral nephrectomy and contralateral heminephrectomy in extremely severe autosomal dominant polycystic kidney disease (ADPKD), which corresponds to the Mayo imaging classification classes 1D and 1E.MATERIALS AND METHODS: We retrospectively reviewed patients who underwent unilateral nephrectomy and contralateral heminephrectomy at the Seoul National University Hospital (Seoul, Korea) between May 1, 2016 and August 1, 2021. The preoperative kidney volume was calculated using the ellipsoid equation (length×width×thickness×π/6). The Mayo imaging classification was determined by height-adjusted total kidney volume and age. Using a midline vertical incision, heminephrectomy was performed first by horizontal transection, followed by contralateral nephrectomy. Hilar vessel clamping or resection-bed suturing was not required.
    RESULTS: In all, nine patients with ADPKD of the highest severity (Mayo class 1D/1E) underwent unilateral heminephrectomy and contralateral nephrectomy for the most common cause of severe abdominal discomfort and malnutrition. All nine patients had end-stage renal disease with hypertension and anemia. The median preoperative total kidney volume was 10,905.8 mL (interquartile range [IQR], 8,170.4-16,227.6 mL). The median operation time was 140 minutes (IQR, 125-185 min) and the median estimated blood loss was 250 mL (IQR, 200-425 mL). Eight of the nine patients were discharged without ICU care or any complications. Delayed pseudoaneurysm occurred in one case and was successfully managed by embolization. All patients were symptom-free for a median follow-up period of 2 years.
    CONCLUSIONS: Synchronous unilateral nephrectomy and contralateral heminephrectomy are safe and feasible treatment options for severe bilateral ADPKD.
    Keywords:  ADPKD; Feasibility study; Heminephrectomy; Safety
    DOI:  https://doi.org/10.4111/icu.20210461
  3. Int J Mol Sci. 2022 Apr 08. pii: 4122. [Epub ahead of print]23(8):
    Perspectives for Primary Ciliary Dyskinesia.
    Zuzanna Bukowy-Bieryllo, Michal Witt, Ewa Zietkiewicz.
      Primary ciliary dyskinesia (PCD) is a ciliopathy caused by genetically determined impairment of motile cilia-organelles present on the surface of many types of cells [...].
    DOI:  https://doi.org/10.3390/ijms23084122
  4. Medicines (Basel). 2022 Mar 29. pii: 25. [Epub ahead of print]9(4):
    Novel PKD2 Missense Mutation p.Ile424Ser in an Individual with Multiple Hepatic Cysts: A Case Report.
    Seiko Miura, Yo Niida, Chieko Hashizume, Ai Fujii, Yuta Takagaki, Kahoru Kusama, Sumiyo Akazawa, Tetsuya Minami, Tsuyoshi Mukai, Kengo Furuichi, Mutsumi Tsuchishima, Nobuhiko Ueda, Hiroyuki Takamura, Daisuke Koya, Tohru Ito.
      We report a novel missense mutation, p.Ile424Ser, in the PKD2 gene of an autosomal dominant polycystic kidney disease (ADPKD) patient with multiple liver cysts. A 57-year-old woman presented to our university hospital with abdominal fullness, decreasing appetite, and dyspnea for three months. A percutaneous drainage of hepatic cysts was performed with no significant symptomatic relief. A computed tomography (CT) scan revealed a hepatic cyst in the lateral portion of the liver with appreciable compression of the stomach. Prior to this admission, the patient had undergone three drainage procedures with serial CT-based follow-up of the cysts over the past 37 years. With a presumptive diagnosis of extrarenal manifestation of ADPKD, we performed both a hepatic cystectomy and a hepatectomy. Because the patient reported a family history of hepatic cysts, we conducted a postoperative genetic analysis. A novel missense mutation, p.Ile424Ser, was detected in the PKD2 gene. Mutations in either the PKD1 or PKD2 genes account for most cases of ADPKD. To the extent of our knowledge, this point mutation has not been reported in the general population. Our in-silico analysis suggests a hereditary likely pathogenic mutation.
    Keywords:  PKD2 (polycystic kidney disease type 2); autosomal dominant polycystic kidney disease (ADPKD); estrogen; polycystic liver
    DOI:  https://doi.org/10.3390/medicines9040025
  5. Bio Protoc. 2022 Mar 20. 12(6): e4360
    3D-Structured Illumination Microscopy of Centrosomes in Human Cell Lines.
    Kari-Anne M Frikstad, Kay O Schink, Sania Gilani, Lotte B Pedersen, Sebastian Patzke.
      The centrosome is the main microtubule-organizing center of animal cells, and is composed of two barrel-shaped microtubule-based centrioles embedded in protein dense pericentriolar material. Compositional and architectural re-organization of the centrosome drives its duplication, and enables its microtubule-organizing activity and capability to form the primary cilium, which extends from the mature (mother) centriole, as the cell exits the cell cycle. Centrosomes and primary cilia are essential to human health, signified by the causal role of centrosome- and cilia-aberrations in numerous congenic disorders, as well as in the etiology and progression of cancer. The list of disease-associated centrosomal proteins and their proximitomes is steadily expanding, emphasizing the need for high resolution mapping of such proteins to specific substructures of the organelle. Here, we provide a detailed 3D-structured illumination microscopy (3D-SIM) protocol for comparative localization analysis of fluorescently labeled proteins at the centrosome in fixed human cell lines, at approximately 120 nm lateral and 300 nm axial resolution. The procedure was optimized to work with primary antibodies previously known to depend on more disruptive fixation reagents, yet largely preserves centriole and centrosome architecture, as shown by transposing acquired images of landmark proteins on previously published transmission electron microscopy (TEM) images of centrosomes. Even more advantageously, it is compatible with fluorescent protein tags. Finally, we introduce an internal reference to ensure correct 3D channel alignment. This protocol hence enables flexible, swift, and information-rich localization and interdependence analyses of centrosomal proteins, as well as their disorder-associated mutations.
    Keywords:  3D-SIM; Centriole; Centrosome; Cilia; Fluorescence microscopy; Super-resolution microscopy
    DOI:  https://doi.org/10.21769/BioProtoc.4360
  6. Cerebellum. 2022 Apr 19.
    The Primary Ciliary Deficits in Cerebellar Bergmann Glia of the Mouse Model of Fragile X Syndrome.
    Bumwhee Lee, Laura Beuhler, Hye Young Lee.
      Primary cilia are non-motile cilia that function as antennae for cells to sense signals. Deficits of primary cilia cause ciliopathies, leading to the pathogenesis of various developmental disorders; however, the contribution of primary cilia to neurodevelopmental disorders is largely unknown. Fragile X syndrome (FXS) is a genetically inherited disorder and is the most common known cause of autism spectrum disorders. FXS is caused by the silencing of the fragile X mental retardation 1 (FMR1) gene, which encodes for the fragile X mental retardation protein (FMRP). Here, we discovered a reduction in the number of primary cilia and the Sonic hedgehog (Shh) signaling in cerebellar Bergmann glia of Fmr1 KO mice. We further found reduced granule neuron precursor (GNP) proliferation and thickness of the external germinal layer (EGL) in Fmr1 KO mice, implicating that primary ciliary deficits in Bergmann glia may contribute to cerebellar developmental phenotypes in FXS, as Shh signaling through primary cilia in Bergmann glia is known to mediate proper GNP proliferation in the EGL. Taken together, our study demonstrates that FMRP loss leads to primary ciliary deficits in cerebellar Bergmann glia which may contribute to cerebellar deficits in FXS.
    Keywords:  Bergmann glia; Cerebellum; FMRP; Fragile X syndrome; Primary cilia
    DOI:  https://doi.org/10.1007/s12311-022-01382-8
  7. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Apr 10. 39(4): 433-437
    [Pathogenic genes and corresponding ciliary defects associated with primary ciliary dyskinesia].
    Lina Wang, Baoping Xu, Liwei Gao.
      Primary ciliary dyskinesia (PCD) is a recessive genetic disorder of motile cilia with substantial genetic and phenotypic heterogeneity. Clinical features of PCD vary from one patient to another, and no single test has the sensitivity and specificity to accurately diagnose PCD. Genetic testing combined with other auxiliary tests can facilitate the confirmatory diagnosis of PCD. So far more than 40 genes have been associated with PCD, but most research have focused on common genes, which hinders our understanding of other rare PCD-genes. This review has summarized the PCD-associated genes and the corresponding characteristics of dysfunctional cilia, with an aim to provide a basis for early identification of such diseases.
    DOI:  https://doi.org/10.3760/cma.j.cn511374-20201222-00898
  8. Biochem Biophys Res Commun. 2022 Apr 14. pii: S0006-291X(22)00573-3. [Epub ahead of print]610 85-91
    Impairment of ciliary dynamics in an APP knock-in mouse model of Alzheimer's disease.
    Yuki Kobayashi, Shogo Kohbuchi, Noriko Koganezawa, Yuko Sekino, Tomoaki Shirao, Takaomi C Saido, Takashi Saito, Yumiko Saito.
      The primary cilium is a specialized microtubule-based sensory organelle that extends from the cell body of nearly all cell types. Neuronal primary cilia, which have their own unique signaling repertoire, are crucial for neuronal integrity and the maintenance of neuronal connectivity throughout adulthood. Dysfunction of cilia structure and ciliary signaling is associated with a variety of genetic syndromes, termed ciliopathies. One of the characteristic features of human ciliopathies is impairment of memory and cognition, which is also observed in Alzheimer's disease (AD). Amyloid β peptide (Aβ) is produced through the proteolytic processing of amyloid precursor protein (APP), and Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of AD. To evaluate the effect of increased Aβ level on primary cilia, we assessed ciliary dynamics in hippocampal neurons in an APP knock-in AD model (AppNL-G-F mice) compared to that in wild-type mice. Neuronal cilia length in the CA1, CA3, and dentate gyrus (DG) of wild-type mice increased significantly with age. In AppNL-G-F mice, such elongation was detected in the DG but not in the CA1 and CA3, where more Aβ accumulation was observed. We further demonstrated that Aβ1-42 treatment decreased cilia length both in hTERT-RPE1 cells and dissociated rat hippocampal neurons. There is growing evidence that reduced cilia length is associated with perturbations of synaptic connectivity and dendrite complexity. Thus, our observations raise the important possibility that structural alterations in neuronal cilia might have a role in AD development.
    Keywords:  Alzheimer's disease; Amyloid-beta peptide; Hippocampus; Primary cilia
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.050
  9. J Bone Miner Res. 2022 Apr 21.
    New and unexpected roles for primary cilia in coordinating response to mechanical load in articular and growth plate cartilages.
    R Serra.
      
    DOI:  https://doi.org/10.1002/jbmr.4557
  10. J Comp Neurol. 2022 Apr 17.
    Distribution of prototypical primary cilia markers in subtypes of retinal ganglion cells.
    Tia J Kowal, Onkar S Dhande, Biao Wang, Qing Wang, Ke Ning, Wendy Liu, Nicolas F Berbari, Yang Hu, Yang Sun.
      Loss of retinal ganglion cells (RGCs) underlies several forms of retinal disease including glaucomatous optic neuropathy, a leading cause of irreversible blindness. Several rare genetic disorders associated with cilia dysfunction have retinal degeneration as a clinical hallmark. Much of the focus of ciliopathy associated blindness is on the connecting cilium of photoreceptors; however, RGCs also possess primary cilia. It is unclear what roles RGC cilia play, what proteins and signaling machinery localize to RGC cilia, or how RGC cilia are differentiated across the subtypes of RGCs. To better understand these questions, we assessed the presence or absence of a prototypical cilia marker Arl13b and a widely distributed neuronal cilia marker AC3 in different subtypes of mouse RGCs. Interestingly, not all RGC subtype cilia are the same and there are significant differences even among these standard cilia markers. Alpha-RGCs positive for osteopontin, calretinin, and SMI32 primarily possess AC3-positive cilia. Directionally selective RGCs that are CART positive or Trhr positive localize either Arl13b or AC3, respectively, in cilia. Intrinsically photosensitive RGCs differentially localize Arl13b and AC3 based on melanopsin expression. Taken together, we characterized the localization of gold standard cilia markers in different subtypes of RGCs and conclude that cilia within RGC subtypes may be differentially organized. Future studies aimed at understanding RGC cilia function will require a fundamental ability to observe the cilia across subtypes as their signaling protein composition is elucidated. A comprehensive understanding of RGC cilia may reveal opportunities to understanding how their dysfunction leads to retinal degeneration.
    Keywords:  AC3; Arl13b; primary cilia; retinal ganglion cells; subtype characterization
    DOI:  https://doi.org/10.1002/cne.25326
  11. Anat Sci Int. 2022 Apr 18.
    Depletion of Ift88 in thymic epithelial cells affects thymic synapse and T-cell differentiation in aged mice.
    Osamu Kutomi, Shigenori Nonaka, Katsuto Hozumi, Sén Takeda.
      Primary cilia are ubiquitous hair-like organelles, usually projecting from the cell surface. They are essential for the organogenesis and homeostasis of various physiological functions, and their dysfunction leads to a plethora of human diseases. However, there are few reports on the role of primary cilia in the immune system; therefore, we focused on their role in the thymus that nurtures immature lymphocytes to full-fledged T cells. We detected primary cilia on the thymic epithelial cell (TEC) expressing transforming growth factor β (TGF-β) receptor in the basal body, and established a line of an intraflagellar transport protein 88 (Ift88) knockout mice lacking primary cilia in TECs (Ift88-TEC null mutant) to clarify their precise role in thymic organogenesis and T-cell differentiation. The Ift88-TEC null mutant mice showed stunted cilia or lack of cilia in TECs. The intercellular contact between T cells and the "thymic synapse" of medullary TECs was slightly disorganized in Ift88-TEC null mutants. Notably, the CD4- and CD8-single positive thymocyte subsets increased significantly. The absence or disorganization of thymic cilia downregulated the TGF-β signaling cascade, increasing the number of single positive thymocytes. To our knowledge, this is the first study reporting the physiological role of primary cilia and Ift88 in regulating the differentiation of the thymus and T cells.
    Keywords:  Ift88; Primary cilia; T cell; TGF-β signaling; Thymic epithelial cells
    DOI:  https://doi.org/10.1007/s12565-022-00663-w
  12. Nat Commun. 2022 Apr 19. 13(1): 2056
    Microridge-like structures anchor motile cilia.
    Takayuki Yasunaga, Johannes Wiegel, Max D Bergen, Martin Helmstädter, Daniel Epting, Andrea Paolini, Özgün Çiçek, Gerald Radziwill, Christina Engel, Thomas Brox, Olaf Ronneberger, Peter Walentek, Maximilian H Ulbrich, Gerd Walz.
      Several tissues contain cells with multiple motile cilia that generate a fluid or particle flow to support development and organ functions; defective motility causes human disease. Developmental cues orient motile cilia, but how cilia are locked into their final position to maintain a directional flow is not understood. Here we find that the actin cytoskeleton is highly dynamic during early development of multiciliated cells (MCCs). While apical actin bundles become increasingly more static, subapical actin filaments are nucleated from the distal tip of ciliary rootlets. Anchorage of these subapical actin filaments requires the presence of microridge-like structures formed during MCC development, and the activity of Nonmuscle Myosin II. Optogenetic manipulation of Ezrin, a core component of the microridge actin-anchoring complex, or inhibition of Myosin Light Chain Kinase interfere with rootlet anchorage and orientation. These observations identify microridge-like structures as an essential component of basal body rootlet anchoring in MCCs.
    DOI:  https://doi.org/10.1038/s41467-022-29741-3
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