bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–09–10
seventeen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. An update on treatments for autosomal dominant polycystic kidney disease: Erratum.
  2. Plant-derived compounds for treating autosomal dominant polycystic kidney disease.
  3. Many lessons still to learn about autosomal dominant polycystic kidney disease.
  4. Polycystin-1 Interacting Protein-1 (CU062) Interacts with the Ectodomain of Polycystin-1 (PC1).
  5. Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins.
  6. Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.
  7. The G protein alpha Chaperone and Guanine-Nucleotide Exchange Factor RIC-8 Regulates Cilia Morphogenesis in Caenorhabditis elegans Sensory Neurons.
  8. The Scaffold Protein KATNIP Enhances CILK1 Control of Primary Cilia.
  9. ODF2 Negatively Regulates CP110 Levels at the Centrioles/Basal Bodies to Control the Biogenesis of Primary Cilia.
  10. Differences in eConsent among diagnosis groups.
  11. HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells.
  12. Osteocytes and Primary Cilia.
  13. Primary cilium-mediated signaling cascade suppresses age-related biliary fibrosis.
  14. A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation.
  15. Beta cell primary cilia mediate somatostatin responsiveness via SSTR3.
  16. Editorial: Global excellence in nephrology: Asia and Australasia.
  17. Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease.
  1. JAAPA. 2023 Sep 01. 36(9): 1
    An update on treatments for autosomal dominant polycystic kidney disease: Erratum.
      
    DOI:  https://doi.org/10.1097/01.JAA.0000977908.45059.48
  2. Front Nephrol. 2023 ;3 1071441
    Plant-derived compounds for treating autosomal dominant polycystic kidney disease.
    Jieting Zhang, Jiaxin Chen, Jing Xu, Cheng Xue, Zhiguo Mao.
      Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic hereditary kidney disease, is the fourth leading cause of end-stage kidney disease worldwide. In recent years, significant progress has been made in delaying ADPKD progression with different kinds of chemical drugs, such as tolvaptan, rapamycin, and somatostatin. Meanwhile, numerous plant-derived compounds have been investigated for their beneficial effects on slowing ADPKD progression. Among them, saikosaponin-d, Ganoderma triterpenes, curcumin, ginkgolide B, steviol, resveratrol, Sparganum stoloniferum Buch.-Ham, Cordyceps sinensis, triptolide, quercitrin, naringin, cardamonin, gambogic acid, and olive leaf extract have been found to retard renal cyst development by inhibiting cell proliferation or promoting cell apoptosis in renal cyst-lining epithelial cells. Metformin, a synthesized compound derived from French lilac or goat's rue (Galega officinalis), has been proven to retard the progression of ADPKD. This review focuses on the roles and mechanisms of plant-derived compounds in treating ADPKD, which may constitute promising new therapeutics in the future.
    Keywords:  herbal medicine; mechanism; plant-derived compounds; polycystic kidney disease; treatment
    DOI:  https://doi.org/10.3389/fneph.2023.1071441
  3. J Rare Dis (Berlin). 2023 ;2(1): 13
    Many lessons still to learn about autosomal dominant polycystic kidney disease.
    Sarah Orr, John A Sayer.
      We are still learning the genetic basis for many rare diseases. Here we provide a commentary on the analysis of the genetic landscape of patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), one of the most common genetic kidney diseases. Approaches including both phenotype first and genotype first allows some interesting and informative observations within this disease population. PKD1 and PKD2 are the most frequent genetic causes of ADPKD accounting for 78% and 15% respectively, whilst around 7-8% of cases have an alternative genetic diagnosis. These rarer forms include IFT140, GANAB, PKHD1, HNF1B, ALG8, and ALG9. Some previously reported likely pathogenic PKD1 and PKD2 alleles may have a reduced penetrance, or indeed may have been misclassified in terms of their pathogenicity. This recent data concerning all forms of ADPKD points to the importance of performing genetics tests in all families with a clinical diagnosis of ADPKD as well as those with more atypical cystic kidney appearances. Following allele identification, performing segregation analysis wherever possible remains vital so that we continue to learn about these important genetic causes of kidney failure.
    Keywords:  ADPKD; Penetrance; Prevalence; Rare Disease; Whole Exome Sequencing
    DOI:  https://doi.org/10.1007/s44162-023-00017-8
  4. Cells. 2023 Aug 29. pii: 2166. [Epub ahead of print]12(17):
    Polycystin-1 Interacting Protein-1 (CU062) Interacts with the Ectodomain of Polycystin-1 (PC1).
    Wendy A Lea, Thomas Winklhofer, Lesya Zelenchuk, Madhulika Sharma, Jessica Rossol-Allison, Timothy A Fields, Gail Reif, James P Calvet, Jason L Bakeberg, Darren P Wallace, Christopher J Ward.
      The PKD1 gene, encoding protein polycystin-1 (PC1), is responsible for 85% of cases of autosomal dominant polycystic kidney disease (ADPKD). PC1 has been shown to be present in urinary exosome-like vesicles (PKD-ELVs) and lowered in individuals with germline PKD1 mutations. A label-free mass spectrometry comparison of urinary PKD-ELVs from normal individuals and those with PKD1 mutations showed that several proteins were reduced to a degree that matched the decrease observed in PC1 levels. Some of these proteins, such as polycystin-2 (PC2), may be present in a higher-order multi-protein assembly with PC1-the polycystin complex (PCC). CU062 (Q9NYP8) is decreased in ADPKD PKD-ELVs and, thus, is a candidate PCC component. CU062 is a small glycoprotein with a signal peptide but no transmembrane domain and can oligomerize with itself and interact with PC1. We investigated the localization of CU062 together with PC1 and PC2 using immunofluorescence (IF). In nonconfluent cells, all three proteins were localized in close proximity to focal adhesions (FAs), retraction fibers (RFs), and RF-associated extracellular vesicles (migrasomes). In confluent cells, primary cilia had PC1/PC2/CU062 + extracellular vesicles adherent to their plasma membrane. In cells exposed to mitochondrion-decoupling agents, we detected the development of novel PC1/CU062 + ring-like structures that entrained swollen mitochondria. In contact-inhibited cells under mitochondrial stress, PC1, PC2, and CU062 were observed on large, apically budding extracellular vesicles, where the proteins formed a reticular network on the membrane. CU062 interacts with PC1 and may have a role in the identification of senescent mitochondria and their extrusion in extracellular vesicles.
    Keywords:  C21orf62; autosomal dominant polycystic kidney disease (ADPKD); collecting duct; exosomes; ligand; migrasomes; polycystin-2; primary cilia; proximal tubule
    DOI:  https://doi.org/10.3390/cells12172166
  5. Int J Mol Sci. 2023 Aug 26. pii: 13278. [Epub ahead of print]24(17):
    Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins.
    Karl Kunzelmann, Jiraporn Ousingsawat, Andre Kraus, Julien H Park, Thorsten Marquardt, Rainer Schreiber, Björn Buchholz.
      The Cl--transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore concentrate on recent findings concerning electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Special emphasis will be placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. In essence, we will summarize recent evidence indicating that CFTR is the only relevant secretory Cl- channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. Information is provided on the expressions of ANO1 and ANO6, which are important for the correct expression and function of CFTR. In addition, there is evidence that the Cl- transporter SLC26A9 expressed in the airways may have a reabsorptive rather than a Cl--secretory function. In the renal collecting ducts, bicarbonate secretion occurs through a synergistic action of CFTR and the Cl-/HCO3- transporter SLC26A4 (pendrin), which is probably supported by ANO1. Finally, in autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have now been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease.
    Keywords:  CFTR; SLC26A9; TMEM16A; TMEM16F; anoctamin; pendrin
    DOI:  https://doi.org/10.3390/ijms241713278
  6. Front Nephrol. 2022 ;2 984165
    Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.
    Eleftherios Gkekas, Tsz Yau Tiffany Tang, Alan Green, Han Davidson, Rachel Fraser, John A Sayer, Shalabh Srivastava.
      Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.
    Keywords:  ADPKD (autosomal dominant polycystic kidney disease); disease progression; end stage kidney disease (ESKD); real world; tolvaptan treatment
    DOI:  https://doi.org/10.3389/fneph.2022.984165
  7. bioRxiv. 2023 Aug 26. pii: 2023.08.25.554856. [Epub ahead of print]
    The G protein alpha Chaperone and Guanine-Nucleotide Exchange Factor RIC-8 Regulates Cilia Morphogenesis in Caenorhabditis elegans Sensory Neurons.
    Christina M Campagna, Hayley McMahon, Inna Nechipurenko.
      Heterotrimeric G (αβγ) proteins are canonical transducers of G-protein-coupled receptor (GPCR) signaling and play critical roles in communication between cells and their environment. Many GPCRs and heterotrimeric G proteins localize to primary cilia and modulate cilia morphology via mechanisms that are not well understood. Here, we show that RIC-8, a cytosolic guanine nucleotide exchange factor (GEF) and chaperone for Gα protein subunits, shapes cilia membrane morphology in a subset of Caenorhabditis elegans sensory neurons. Consistent with its role in ciliogenesis, C. elegans RIC-8 localizes to cilia in different sensory neuron types. Using domain mutagenesis, we demonstrate that while the GEF function alone is not sufficient, both the GEF and Gα-interacting chaperone motifs of RIC-8 are required for its role in cilia morphogenesis. We identify ODR-3 as the RIC-8 Gα client and demonstrate that RIC-8 functions in the same genetic pathway with another component of the non-canonical G protein signaling AGS-3 to shape cilia morphology. Notably, despite severe defects in AWC cilia morphology, ags-3 null mutants exhibit normal chemotaxis toward benzaldehyde unlike odr-3 mutant animals. Collectively, our findings describe a novel function for the evolutionarily conserved protein RIC-8 and non-canonical RIC-8-AGS-3-ODR-3 signaling in cilia morphogenesis and uncouple Gα ODR-3 functions in ciliogenesis and olfaction.
    Author Summary: Primary cilia are specialized cellular compartments that mediate communication between cells and their environment. In humans, deficits in cilia assembly and function lead to genetic diseases called ciliopathies. While the molecular machinery that sends out and receives major signaling cues is present inside cilia of different cell types, the mechanisms by which these signaling factors modulate cilia structure or cilia-dependent cellular functions are not well understood. In this study, we identify a new role for the RIC-8-AGS-3-ODR-3 signaling module in formation of specialized ciliary structures in C. elegans neurons. Our findings provide new insight into mechanisms of cilia assembly and highlight how the same signaling component (i.e. ODR-3) can be differentially regulated to mediate distinct cellular functions (cilia formation versus olfactory behavior).
    DOI:  https://doi.org/10.1101/2023.08.25.554856
  8. Mol Cell Biol. 2023 Sep 04. 1-9
    The Scaffold Protein KATNIP Enhances CILK1 Control of Primary Cilia.
    Jacob S Turner, Ellie A McCabe, Kevin W Kuang, Casey D Gailey, David L Brautigan, Ana Limerick, Elena X Wang, Zheng Fu.
      The primary cilium functions as a cellular sensory organelle and signaling antenna that detects and transduces extracellular signals. Mutations in the human gene CILK1 (ciliogenesis associated kinase 1) cause abnormal cilia elongation and faulty Hedgehog signaling, associated with developmental disorders and epilepsy. CILK1 is a protein kinase that requires dual phosphorylation of its TDY motif for activation and its extended C-terminal intrinsically disordered region (IDR) mediates targeting to the basal body and substrate recognition. Proteomics previously identified katanin-interacting protein (KATNIP), also known as KIAA0556, as a CILK1 interacting partner. In this study we discovered that CILK1 colocalizes with KATNIP at the basal body and the CILK1 IDR is sufficient to mediate binding to KATNIP. Deletion analysis of KATNIP shows one of three domains of unknown function (DUF) is required for association with CILK1. KATNIP binding with CILK1 drastically elevated CILK1 protein levels and TDY phosphorylation in cells. This resulted in a profound increase in phosphorylation of known CILK1 substrates and suppression of cilia length. Thus, KATNIP functions as a regulatory subunit of CILK1 that potentiates its actions. This advances our understanding of the molecular basis of control of primary cilia.
    Keywords:  CILK1; KATNIP; kinase; phosphorylation; primary cilia
    DOI:  https://doi.org/10.1080/10985549.2023.2246870
  9. Cells. 2023 Sep 01. pii: 2194. [Epub ahead of print]12(17):
    ODF2 Negatively Regulates CP110 Levels at the Centrioles/Basal Bodies to Control the Biogenesis of Primary Cilia.
    Madeline Otto, Sigrid Hoyer-Fender.
      Primary cilia are essential sensory organelles that develop when an inhibitory cap consisting of CP110 and other proteins is eliminated. The degradation of CP110 by the ubiquitin-dependent proteasome pathway mediated by NEURL4 and HYLS1 removes the inhibitory cap. Here, we investigated the suitability of rapamycin-mediated dimerization for centriolar recruitment and asked whether the induced recruitment of NEURL4 or HYLS1 to the centriole promotes primary cilia development and CP110 degradation. We used rapamycin-mediated dimerization with ODF2 to induce their targeted recruitment to the centriole. We found decreased CP110 levels in the transfected cells, but independent of rapamycin-mediated dimerization. By knocking down ODF2, we showed that ODF2 controls CP110 levels. The overexpression of ODF2 is not sufficient to promote the formation of primary cilia, but the overexpression of NEURL4 or HYLS1 is. The co-expression of ODF2 and HYLS1 resulted in the formation of tube-like structures, indicating an interaction. Thus, ODF2 controls primary cilia formation by negatively regulating the concentration of CP110 levels. Our data suggest that ODF2 most likely acts as a scaffold for the binding of proteins such as NEURL4 or HYLS1 to mediate CP110 degradation.
    Keywords:  CP110; HYLS1; NEURL4; ODF2; ciliation; rapamycin-induced targeting
    DOI:  https://doi.org/10.3390/cells12172194
  10. Contemp Clin Trials Commun. 2023 Oct;35 101200
    Differences in eConsent among diagnosis groups.
    Deborah Profit, William Carson, Leonard Chuck, Candace Saldarini, Hannah Glenny.
      eConsent is an electronic informed consent experience that contains videos, word flags, and knowledge checks, in addition to an electronic version of the informed consent document to enhance clinical trial participants' understanding of what they are consenting to. There are numerous perceived benefits of eConsent, however despite these benefits, adoption has remained low. eConsent data from 27 clinical trials was analyzed to gain insights and understand differences in the consenting process between diagnosis groups. It was found that those with bipolar disorder spent significantly less time on the instructional video while those with schizophrenia spent significantly more. Participants with autosomal dominant polycystic kidney disease (ADPKD) had the lowest engagement while participants with schizophrenia were the most engaged. Knowledge check scores for participants with attention deficit hyperactivity disorder (ADHD) were significantly lower than the other diagnosis groups. The data available through eConsent provides crucial insights into the consenting differences among participants' diagnoses. Understanding these differences will support tailoring the eConsent process to a more patient centric design and ensure study participants understand what they are consenting to.
    Keywords:  Clinical trial; Consent; Informed consent; Patient centricity; eConsent
    DOI:  https://doi.org/10.1016/j.conctc.2023.101200
  11. J Cell Sci. 2024 03 01. pii: jcs261047. [Epub ahead of print]137(5):
    HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells.
    Huxley K Hoffman, Rytis Prekeris.
      Primary cilia are sensory cellular organelles crucial for organ development and homeostasis. Ciliogenesis in polarized epithelial cells requires Rab19-mediated clearing of apical cortical actin to allow the cilium to grow from the apically docked basal body into the extracellular space. Loss of the lysosomal membrane-tethering homotypic fusion and protein sorting (HOPS) complex disrupts this actin clearing and ciliogenesis, but it remains unclear how the ciliary function of HOPS relates to its canonical function in regulating late endosome-lysosome fusion. Here, we show that disruption of HOPS-dependent lysosomal fusion indirectly impairs actin clearing and ciliogenesis by disrupting the targeting of Rab19 to the basal body, and that this effect is specific to polarized epithelial cells. We also find that Rab19 functions in endolysosomal cargo trafficking in addition to having its previously identified role in ciliogenesis. In summary, we show that inhibition of lysosomal fusion leads to the abnormal accumulation of Rab19 on late endosomes, thus depleting Rab19 from the basal body and thereby disrupting Rab19-mediated actin clearing and ciliogenesis in polarized epithelial cells.
    Keywords:  Cilia; Epithelial polarity; HOPS complex; Lysosomal fusion; Rab19; Renal epithelia
    DOI:  https://doi.org/10.1242/jcs.261047
  12. Curr Osteoporos Rep. 2023 Sep 08.
    Osteocytes and Primary Cilia.
    Stefaan W Verbruggen, Anuphan Sittichokechaiwut, Gwendolen C Reilly.
       PURPOSE OF REVIEW: The purpose of this review is to provide a background on osteocytes and the primary cilium, discussing the role it plays in osteocyte mechanosensing.
    RECENT FINDINGS: Osteocytes are thought to be the primary mechanosensing cells in bone tissue, regulating bone adaptation in response to exercise, with the primary cilium suggested to be a key mechanosensing mechanism in bone. More recent work has suggested that, rather than being direct mechanosensors themselves, primary cilia in bone may instead form a key chemo-signalling nexus for processing mechanoregulated signalling pathways. Recent evidence suggests that pharmacologically induced lengthening of the primary cilium in osteocytes may potentiate greater mechanotransduction, rather than greater mechanosensing. While more research is required to delineate the specific osteocyte mechanobiological molecular mechanisms governed by the primary cilium, it is clear from the literature that the primary cilium has significant potential as a therapeutic target to treat mechanoregulated bone diseases, such as osteoporosis.
    Keywords:  Biomechanics; Bone; Mechanobiology; Osteocyte; Primary cilium
    DOI:  https://doi.org/10.1007/s11914-023-00819-1
  13. J Cell Physiol. 2023 Sep 08.
    Primary cilium-mediated signaling cascade suppresses age-related biliary fibrosis.
    Renjie Hong, Xiaoyu Tian, Hongbo Ma, Hua Ni, Jia Yang, Weiwen Bu, Te Li, Song Yang, Dengwen Li, Min Liu, Yanjie Tan.
      The primary cilium is increasingly recognized as a crucial player in the physiology of biliary epithelial cells (BECs). However, the precise role of primary cilia in the development of age-related biliary fibrosis remains unclear. Herein, using cilium-deficient mice, we demonstrate that disruption of ciliary homeostasis in BECs in aged mice leads to significant bile duct proliferation, augmented biliary fibrosis, and heightened indicators of liver injury. Our RNA-sequencing data revealed a dysregulation in genes associated with various biological processes such as bile secretion, fatty acid metabolism, and inflammation. Loss of primary cilia also significantly enhanced signaling pathways driving the development of biliary fibrosis. Our findings collectively suggest that loss of primary cilia in the BECs of aged mice initiates a cascade of signaling events that contribute to biliary fibrosis, highlighting the primary cilium as a potential therapeutic target in the treatment of fibrosing cholangiopathies.
    Keywords:  aged mouse; biliary epithelial cell; biliary fibrosis; primary cilium; signaling
    DOI:  https://doi.org/10.1002/jcp.31113
  14. BMC Genomics. 2023 Sep 04. 24(1): 521
    A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation.
    Cuiting Peng, Han Chen, Jun Ren, Fan Zhou, Yutong Li, Yuezhi Keqie, Taoli Ding, Jiangxing Ruan, He Wang, Xinlian Chen, Shanling Liu.
      The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.
    Keywords:  ADPKD; De novo mutation; Long read sequencing; PGT-M; SNP haplotype
    DOI:  https://doi.org/10.1186/s12864-023-09593-x
  15. Islets. 2023 12 31. 15(1): 2252855
    Beta cell primary cilia mediate somatostatin responsiveness via SSTR3.
    Samantha E Adamson, Zipeng A Li, Jing W Hughes.
      Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically encoded beta cell-specific GCaMP6f calcium reporter shows that somatostatin signaling alters beta cell calcium flux after physiologic glucose stimulation, an effect that depends on endogenous SSTR3 expression and the presence of intact primary cilia on beta cells. Comparative in vitro studies using SSTR isoform antagonists demonstrate a role for SSTR3 in mediating somatostatin regulation of insulin secretion in mouse islets. Our findings support a model in which ciliary SSTR3 mediates a distinct pathway of delta-to-beta cell regulatory crosstalk and may serve as a target for paracrine modulation.
    Keywords:  SSTR3; beta cell; calcium; islet; primary cilia, somatostatin
    DOI:  https://doi.org/10.1080/19382014.2023.2252855
  16. Front Nephrol. 2023 ;3 1248728
    Editorial: Global excellence in nephrology: Asia and Australasia.
    Cheng Xue, Mingxi Li, Suxia Wang.
      
    Keywords:  IgA nephropathy; chronic kidney disease; end-stage kidney disease; minimal change disease; polycystic kidney disease
    DOI:  https://doi.org/10.3389/fneph.2023.1248728
  17. Acta Neuropathol Commun. 2023 Sep 04. 11(1): 142
    Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease.
    Jaemyung Jang, Seungeun Yeo, Soonbong Baek, Hyun Jin Jung, Mi Suk Lee, Seung Hee Choi, Youngshik Choe.
      Dystrophic neurites (DNs) are abnormal axons and dendrites that are swollen or deformed in various neuropathological conditions. In Alzheimer's disease (AD), DNs play a crucial role in impairing neuronal communication and function, and they may also contribute to the accumulation and spread of amyloid beta (Aβ) in the brain of AD patients. However, it is still a challenge to understand the DNs of specific neurons that are vulnerable to Aβ in the pathogenesis of AD. To shed light on the development of radiating DNs, we examined enriched dystrophic hippocampal axons in a mouse model of AD using a three-dimensional rendering of projecting neurons. We employed the anterograde spread of adeno-associated virus (AAV)1 and conducted proteomic analysis of synaptic compartments obtained from hippocampo-septal regions. Our findings revealed that DNs were formed due to synaptic loss at the axon terminals caused by the accumulation of extracellular vesicle (EV). Abnormal EV-mediated transport and exocytosis were identified in association with primary cilia, indicating their involvement in the accumulation of EVs at presynaptic terminals. To further address the regulation of DNs by primary cilia, we conducted knockdown of the Ift88 gene in hippocampal neurons, which impaired EV-mediated secretion of Aβ and promoted accumulation of axonal spheroids. Using single-cell RNA sequencing, we identified the septal projecting hippocampal somatostatin neurons (SOM) as selectively vulnerable to Aβ with primary cilia dysfunction and vesicle accumulation. Our study suggests that DNs in AD are initiated by the ectopic accumulation of EVs at the neuronal axon terminals, which is affected by neuronal primary cilia.
    Keywords:  Dystrophic neurites; Extracellular vesicles; Hippocampal septal connection; Primary cilia; Selectively vulnerable neurons; Single cell RNA sequencing
    DOI:  https://doi.org/10.1186/s40478-023-01637-3
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