bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒08‒15
seventeen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Short-term changes in micturition patterns with tolvaptan treatment for autosomal dominant polycystic kidney disease.
  2. Twenty-Year Survival of Kidney Transplant From a Deceased Donor With Autosomal Dominant Polycystic Kidney Disease.
  3. Case report-Campylobacter jejuni cyst infection in autosomal dominant polycystic kidney disease.
  4. Tolvaptan in ADPKD Patients With Very Low Kidney Function.
  5. The BC ADPKD Network: A Comprehensive Provincial Approach to Support Specialized and Locally Delivered Multidisciplinary ADPKD Care.
  6. Systematic review on outcomes used in clinical research on autosomal recessive polycystic kidney disease-are patient-centered outcomes our blind spot?
  7. INPP5E controls ciliary localization of phospholipids and the odor response in olfactory sensory neurons.
  8. The causes and consequences of paediatric kidney disease on adult nephrology care.
  9. Role of Rho-Associated Protein Kinase Inhibition As Therapeutic Strategy for Parkinson's Disease: Dopaminergic Survival and Enhanced Mitophagy.
  10. Kidney Organoid and Microphysiological Kidney Chip Models to Accelerate Drug Development and Reduce Animal Testing.
  11. Oral-facio-digital syndrome type I: In the differential diagnosis of autosomic dominant polycystic kidney disease, about three cases.
  12. Emerging targets in drug discovery against neurodegenerative diseases: Control of synapsis disfunction by the RhoA/ROCK pathway.
  13. Robotic-assisted Kidney Transplantation With Simultaneous Bilateral Nephrectomies Is an Efficient, Feasible, and Safe Way to Manage Patients With Renal Failure Secondary to Adult Polycystic Kidney Disease.
  14. Structural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel.
  15. Enhanced RhoA signaling stabilizes E-cadherin in migrating epithelial monolayers.
  16. Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts.
  17. Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis.
  1. Asian J Surg. 2021 Aug 07. pii: S1015-9584(21)00432-2. [Epub ahead of print]
    Short-term changes in micturition patterns with tolvaptan treatment for autosomal dominant polycystic kidney disease.
    Takashi Hatano, Katsuhisa Endo.
      
    Keywords:  Autosomal dominant polycystic kidney disease; Circadian rhythm; Micturition pattern; Nocturnal polyuria; Residual urine volume; Tolvaptan
    DOI:  https://doi.org/10.1016/j.asjsur.2021.06.050
  2. Kidney Int Rep. 2021 Aug;6(8): 2240-2242
    Twenty-Year Survival of Kidney Transplant From a Deceased Donor With Autosomal Dominant Polycystic Kidney Disease.
    Naim Issa, Maroun Chedid, Maria V Irazabal, Patrick G Dean, Fouad T Chebib.
      
    DOI:  https://doi.org/10.1016/j.ekir.2021.05.030
  3. Nephrology (Carlton). 2021 Aug 11.
    Case report-Campylobacter jejuni cyst infection in autosomal dominant polycystic kidney disease.
    Ezekiel Kingston, Isaline Goemaere, Michael Kvopka, Sarah Coghill, Sanjeev Baweja.
      
    DOI:  https://doi.org/10.1111/nep.13956
  4. Kidney Int Rep. 2021 Aug;6(8): 2171-2178
    Tolvaptan in ADPKD Patients With Very Low Kidney Function.
    Vicente E Torres, Ron T Gansevoort, Ronald D Perrone, Arlene B Chapman, John Ouyang, Jennifer Lee, Hina Japes, Ali Nourbakhsh, Tao Wang.
      Introduction: Tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) in TEMPO 3:4 and REPRISE trials. Tolvaptan effects in subjects with eGFR 15 to 24 ml/min per 1.73 m2 were not investigated. This post hoc analysis retrospectively investigated eGFR decline in REPRISE versus an open-label, phase 3b extension trial (open-label extension [OLE] NCT02251275) in subjects who received placebo in REPRISE and tolvaptan in OLE with eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2, respectively.Methods: One data subset comprised subjects with OLE baseline eGFR 15 to 29 ml/min per 1.73 m2 who had received placebo in REPRISE and began tolvaptan in OLE. The second comprised subjects who had received tolvaptan in REPRISE and were matched to REPRISE placebo-treated subjects for REPRISE baseline characteristics. Annualized eGFR slopes in REPRISE versus OLE were compared within the REPRISE placebo (i.e., placebo vs. tolvaptan treatment) and tolvaptan (i.e., 2 periods of tolvaptan treatment) subsets.
    Results: Mean annualized eGFR slopes (ml/min per 1.73 m2) during tolvaptan treatment in OLE versus placebo treatment in REPRISE were -3.4 versus -5.2 for subjects with OLE baseline eGFR 15 to 29 (difference, 1.7; P < 0.001), -3.6 versus -5.4 with baseline eGFR 15 to 24 (difference, 1.8; P < 0.001), and -3.3 versus -4.9 with baseline eGFR 25 to 29 (difference, 1.6; P < 0.001). In REPRISE tolvaptan subjects who continued tolvaptan in OLE, treatment effect was maintained (no difference between mean annualized eGFR slopes).
    Conclusion: Initiating or maintaining tolvaptan therapy significantly delayed eGFR decline in subjects with baseline eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2.
    Keywords:  autosomal dominant polycystic kidney disease; chronic kidney disease; clinical trials; glomerular filtration rate; post hoc analysis; tolvaptan
    DOI:  https://doi.org/10.1016/j.ekir.2021.05.037
  5. Can J Kidney Health Dis. 2021 ;8 20543581211035218
    The BC ADPKD Network: A Comprehensive Provincial Approach to Support Specialized and Locally Delivered Multidisciplinary ADPKD Care.
    M Bevilacqua, S Gradin, J Williams, A Romann, C Lo, O Djurdjev, A Levin.
      Purpose: With evolving evidence around the progression, assessment, and management of autosomal dominant polycystic kidney disease (ADPKD), care of the disease has become increasingly complex. Needs assessments in British Columbia (BC) described variability in knowledge and comfort with incorporating these new aspects of ADPKD care into clinical practice. Undercapture of early-stage ADPKD patients in existing renal databases was also identified as an unmet need.Sources of Information: A multidisciplinary group of clinicians and patient partners with interest and expertise in ADPKD and/or multidisciplinary kidney care informed the project work. An existing provincial renal database was used to support the provincial ADPKD registry.
    Methods: A formalized, comprehensive provincial ADPKD Network was created within the existing infrastructure of multidisciplinary kidney clinics (MDCs) in BC. The Network is coordinated provincially and implemented locally. It incorporates robust data collection, education, creation, and dissemination of dedicated clinical tools; collaboration between clinics and clinicians across the province; and ongoing evaluation and continuous quality improvement.
    Key Findings: Over the 5 years since its inception, the BC ADPKD Network has enabled increased and earlier identification of British Columbians living with ADPKD and a shift in practice toward increased and earlier enrollment of ADPKD patients into MDCs. A host of tailored ADPKD clinical tools have been created and implemented in all MDCs across the province to support existing MDC staff in the delivery of more standardized and specialized ADPKD care. A collaborative provincial clinician network founded on Local Clinical Champions has been established to support ongoing experience sharing between clinics. An evaluation framework has been established to evaluate outcomes and enable ongoing refinement of the Network.
    Limitations: The provincial ADPKD registry is undergoing enhancements to enable more comprehensive capture of APDKD-specific information such as total kidney volume and genetic results, but at present, this remains a limitation. It remains to be seen whether the activities of the ADPKD Network will improve long-term clinical outcomes and care experiences of patients living with ADPKD, and a long-term sustainability assessment of this model of care will be required.
    Implications: The structure, tools, and coordinated and collaborative clinician network established through this comprehensive provincial ADPKD Network may be valuable in addressing the variability and gaps in existing ADPKD care while allowing patients and families across BC to receive enhanced care locally, in their usual kidney care environments.
    Keywords:  ADPKD (autosomal dominant polycystic kidney disease); best practices; clinical network; multidisciplinary clinic; standardization
    DOI:  https://doi.org/10.1177/20543581211035218
  6. Pediatr Nephrol. 2021 Aug 12.
    Systematic review on outcomes used in clinical research on autosomal recessive polycystic kidney disease-are patient-centered outcomes our blind spot?
    Charlotte Gimpel, Max Christoph Liebau, Franz Schaefer.
      BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe hepatorenal disease. Survivors of pulmonary hypoplasia and patients with milder presentations often achieve long-term survival but frequently require kidney and/or liver transplantation.OBJECTIVE: To examine the use of clinical, surrogate and patient-centered outcomes in studies on ARPKD with special attention to core outcomes of the Standardized Outcomes in NephroloGy project for children with chronic kidney disease (SONG-Kids).
    DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: A systematic MEDLINE literature search identified 367 ARPKD studies published since 1990; however, of these 134 were excluded because they did not report any clinical outcomes (e.g. only histopathological, genetic, protein structure or radiological markers), 19 studies because they only included prenatal patients and 138 because they were case reports with ≤ 3 patients.
    STUDY APPRAISAL: Seventy-six eligible studies were examined for study type, size, intervention, and reported outcomes by organ system and type, including all SONG-kids tier 1-3 outcomes.
    PARTICIPANTS: There were 3231 patient-reports of children and adults with ARPKD.
    RESULTS: The overwhelming majority of studies reported clinical and surrogate outcomes (75/76 (98%) and 73/76 (96%)), but only 11/76 (14%) examined patient-centered outcomes and only 2/76 (3%) used validated instruments to capture them. Of the SONG-Kids core outcomes, kidney function was reported almost universally (70/76 (92%), infection and survival in three quarters (57/76 (75%), 55/76 (72%)) and measures of life participation (including neurological impairment) only rarely and inconsistently (16/76 (21%)).
    LIMITATIONS: Thirty studies (39%) were of low quality as they were either narrative case reports (n = 14, 18%) and/or patients with ARPKD were an indistinguishable subgroup (n = 18, 24%). Only 28 trials compared interventions, but none were randomized.
    CONCLUSIONS AND IMPLICATIONS: Studies that reported clinical outcomes in ARPKD usually covered the core outcome domains of kidney function, infections, and survival, but measures of life participation and patient-centered outcomes are distinctly lacking and require more attention in future trials. A higher resolution version of the Graphical abstract is available as Supplementary information.
    Keywords:  ARPKD; Outcomes; Patient centered; Patient-reported outcome measures; SONG initiative; Systematic review
    DOI:  https://doi.org/10.1007/s00467-021-05192-8
  7. J Cell Sci. 2022 Mar 01. pii: jcs258364. [Epub ahead of print]135(5):
    INPP5E controls ciliary localization of phospholipids and the odor response in olfactory sensory neurons.
    Kirill Ukhanov, Cedric Uytingco, Warren Green, Lian Zhang, Stephane Schurmans, Jeffrey R Martens.
      The lipid composition of the primary cilia membrane is emerging as a critical regulator of cilia formation, maintenance and function. Here, we show that conditional deletion of the phosphoinositide 5'-phosphatase gene Inpp5e, mutation of which is causative of Joubert syndrome, in terminally developed mouse olfactory sensory neurons (OSNs), leads to a dramatic remodeling of ciliary phospholipids that is accompanied by marked elongation of cilia. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], which is normally restricted to the proximal segment redistributed to the entire length of cilia in Inpp5e knockout mice with a reduction in phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] and elevation of phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] in the dendritic knob. The redistribution of phosphoinositides impaired odor adaptation, resulting in less efficient recovery and altered inactivation kinetics of the odor-evoked electrical response and the odor-induced elevation of cytoplasmic Ca2+. Gene replacement of Inpp5e through adenoviral expression restored the ciliary localization of PI(4,5)P2 and odor response kinetics in OSNs. Our findings support the role of phosphoinositides as a modulator of the odor response and in ciliary biology of native multi-ciliated OSNs.
    Keywords:  INPP5E; Mouse; Odor response; Olfactory cilia; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.258364
  8. Pediatr Nephrol. 2021 Aug 13.
    The causes and consequences of paediatric kidney disease on adult nephrology care.
    Ruth J Pepper, Richard S Trompeter.
      Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.
    Keywords:  CKD; Congenital anomalies of the kidney and urinary tract (CAKUT); Nephrotic; Transition
    DOI:  https://doi.org/10.1007/s00467-021-05182-w
  9. Cureus. 2021 Aug;13(8): e16973
    Role of Rho-Associated Protein Kinase Inhibition As Therapeutic Strategy for Parkinson's Disease: Dopaminergic Survival and Enhanced Mitophagy.
    Huma Quadir, Knkush Hakobyan, Mrunanjali Gaddam, Ugochi Ojinnaka, Zubayer Ahmed, Amudhan Kannan, Jihan A Mostafa.
      The GTP-binding protein, Rho, plays a significant role in the cellular pathology of Parkinson's disease. The downstream effector of Rho, Rho-associated kinase (ROCK), performs several functions, including microglial inflammatory response and enhanced Parkin-mediated mitophagy. Its inhibition shows neuroprotective effects in carried studies. Parkinson's disease pathology also rests on incomplete removal of damaged mitochondria, leading to neuronal impairment. ROCK has different isoforms, inhibition of which have been shown to decrease the adverse changes in microglia. There has also been evidence of a decreased release of inflammatory cytokines and a reduction in degradation of dopaminergic neurons on the addition of ROCK inhibitors. Additionally, ROCK inhibitors have recently been shown to increase the activity of hexokinase 2 (HK2), relocating it to mitochondria, and therefore leading to upregulated mitochondrial targeting. Understanding the cellular basis of ROCK activity and its inhibition may help us advance in creating new strategies for the treatment of Parkinson's disease.
    Keywords:  dopaminergic survival; fasudil; hexokinase; mitophagy; parkin; parkinson’s disease; pink1; rho-associated protein kinase; rock; substantia nigra
    DOI:  https://doi.org/10.7759/cureus.16973
  10. Front Pharmacol. 2021 ;12 695920
    Kidney Organoid and Microphysiological Kidney Chip Models to Accelerate Drug Development and Reduce Animal Testing.
    Wei-Yang Chen, Eric A Evangelista, Jade Yang, Edward J Kelly, Catherine K Yeung.
      Kidneys are critical for the elimination of many drugs and metabolites via the urine, filtering waste and maintaining proper fluid and electrolyte balance. Emerging technologies incorporating engineered three-dimensional (3D) in vitro cell culture models, such as organoids and microphysiological systems (MPS) culture platforms, have been developed to replicate nephron function, leading to enhanced efficacy, safety, and toxicity evaluation of new drugs and environmental exposures. Organoids are tiny, self-organized three-dimensional tissue cultures derived from stem cells that can include dozens of cell types to replicate the complexity of an organ. In contrast, MPS are highly controlled fluidic culture systems consisting of isolated cell type(s) that can be used to deconvolute mechanism and pathophysiology. Both systems, having their own unique benefits and disadvantages, have exciting applications in the field of kidney disease modeling and therapeutic discovery and toxicology. In this review, we discuss current uses of both hPSC-derived organoids and MPS as pre-clinical models for studying kidney diseases and drug induced nephrotoxicity. Examples such as the use of organoids to model autosomal dominant polycystic kidney disease, and the use of MPS to predict renal clearance and nephrotoxic concentrations of novel drugs are briefly discussed. Taken together, these novel platforms allow investigators to elaborate critical scientific questions. While much work needs to be done, utility of these 3D cell culture technologies has an optimistic outlook and the potential to accelerate drug development while reducing the use of animal testing.
    Keywords:  kidney; microfluidic; microphysiologic system; organoids; translational sciences
    DOI:  https://doi.org/10.3389/fphar.2021.695920
  11. Nefrologia. 2021 Aug 07. pii: S0211-6995(21)00141-7. [Epub ahead of print]
    Oral-facio-digital syndrome type I: In the differential diagnosis of autosomic dominant polycystic kidney disease, about three cases.
    Víctor Martínez Jiménez, Pedro Pablo Ortuño López, Susana Roca Meroño, Lidia Rodríguez Peña, Isabel Galán Carrillo, Liliana Galbis Martínez, Fernanda Ramos Carrasco, Juan Alberto Piñero Hernández, Juan David González Rodríguez, Encarnación Guillén Navarro, .
      
    DOI:  https://doi.org/10.1016/j.nefro.2021.03.012
  12. Eur J Med Chem. 2021 Aug 08. pii: S0223-5234(21)00591-2. [Epub ahead of print]225 113742
    Emerging targets in drug discovery against neurodegenerative diseases: Control of synapsis disfunction by the RhoA/ROCK pathway.
    Olmo Martín-Cámara, Ángel Cores, Pilar López-Alvarado, J Carlos Menéndez.
      Synaptic spine morphology is controlled by the activity of Rac1, Cdc42 and RhoA, which need to be finely balanced, and in particular RhoA/ROCK prevents the formation of new protrusions by stabilizing actin formation. These processes are crucial to the maturation process, slowing the de novo generation of new spines. The RhoA/ROCK also influences plasticity processes, and selective modulation by ROCK1 of MLC-dependent actin dynamics leads to neurite retraction, but not to spine retraction. ROCK1 is also responsible for the reduction of the readily releasable pool of synaptic vesicles. These and other evidences suggest that ROCK1 is the main isoform acting on the presynaptic neuron. On the other hand, ROCK2 seems to have broad effects on LIMK/cofilin-dependent plasticity processes such as cofilin-dependent PSD changes. The RhoA/ROCK pathway is an important factor in several different brain-related pathologies via both downstream and upstream pathways. In the aggregate, these evidences show that the RhoA/ROCK pathway has a central role in the etiopathogenesis of a large group of CNS diseases, which underscores the importance of the pharmacological modulation of RhoA/ROCK as an important pathway to drug discovery in the neurodegenerative disease area. This article aims at providing the first review of the role of compounds acting on the RhoA/ROCK pathway in the control of synaptic disfunction.
    Keywords:  Dendritic spines; Neurodegenerative diseases; ROCK inhibitors; Rho kinase; Synaptic disfunction
    DOI:  https://doi.org/10.1016/j.ejmech.2021.113742
  13. Transplant Direct. 2021 Sep;7(9): e740
    Robotic-assisted Kidney Transplantation With Simultaneous Bilateral Nephrectomies Is an Efficient, Feasible, and Safe Way to Manage Patients With Renal Failure Secondary to Adult Polycystic Kidney Disease.
    George Rofaiel, Miklos Z Molnar, Nicholas Baker, Jeffrey Campsen, Robin Kim.
      Kidney transplantation has become the standard of care for end-stage renal disease secondary to adult polycystic kidney disease. Open surgical techniques remain the gold standard, although minimally invasive methods have gained traction in recent years. Native nephrectomy is frequently needed secondary to size or symptoms. Continued developments in surgical technology have allowed for the introduction of computer-assisted surgery (Robotics). We aim to describe the feasibility, safety, and efficiency of simultaneous laparoscopic bilateral nephrectomy and robotic-assisted kidney transplantation to treat end-stage renal kidney transplantation secondary to polycystic kidney disease. In this initial experience, 3 patients underwent kidney transplantation with a simultaneous bilateral nephrectomy. All patients tolerated the procedure well with no postoperative blood transfusions, dialysis, or surgical site infections. Simultaneous laparoscopic bilateral nephrectomy and robotic-assisted kidney transplantation may be feasible, safe, and efficient techniques. Complications were minimal, with short hospital stays. Supplemental Video; http://links.lww.com/TXD/A352.
    DOI:  https://doi.org/10.1097/TXD.0000000000001195
  14. Nat Commun. 2021 08 11. 12(1): 4871
    Structural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel.
    Qiang Su, Mengying Chen, Yan Wang, Bin Li, Dan Jing, Xiechao Zhan, Yong Yu, Yigong Shi.
      The heteromeric complex between PKD1L3, a member of the polycystic kidney disease (PKD) protein family, and PKD2L1, also known as TRPP2 or TRPP3, has been a prototype for mechanistic characterization of heterotetrametric TRP-like channels. Here we show that a truncated PKD1L3/PKD2L1 complex with the C-terminal TRP-fold fragment of PKD1L3 retains both Ca2+ and acid-induced channel activities. Cryo-EM structures of this core heterocomplex with or without supplemented Ca2+ were determined at resolutions of 3.1 Å and 3.4 Å, respectively. The heterotetramer, with a pseudo-symmetric TRP architecture of 1:3 stoichiometry, has an asymmetric selectivity filter (SF) guarded by Lys2069 from PKD1L3 and Asp523 from the three PKD2L1 subunits. Ca2+-entrance to the SF vestibule is accompanied by a swing motion of Lys2069 on PKD1L3. The S6 of PKD1L3 is pushed inward by the S4-S5 linker of the nearby PKD2L1 (PKD2L1-III), resulting in an elongated intracellular gate which seals the pore domain. Comparison of the apo and Ca2+-loaded complexes unveils an unprecedented Ca2+ binding site in the extracellular cleft of the voltage-sensing domain (VSD) of PKD2L1-III, but not the other three VSDs. Structure-guided mutagenic studies support this unconventional site to be responsible for Ca2+-induced channel activation through an allosteric mechanism.
    DOI:  https://doi.org/10.1038/s41467-021-25216-z
  15. J Cell Sci. 2021 Aug 09. pii: jcs.258767. [Epub ahead of print]
    Enhanced RhoA signaling stabilizes E-cadherin in migrating epithelial monolayers.
    Shafali Gupta, Kinga Duszyc, Suzie Verma, Srikanth Budnar, Xuan Liang, Guillermo A Gomez, Philippe Marcq, Ivar Noordstra, Alpha S Yap.
      Epithelia migrate as physically coherent populations of cells. Earlier studies revealed that mechanical stress accumulates in these cellular layers as they move. These stresses are characteristically tensile in nature and have often been inferred to arise when moving cells pull upon the cell-cell adhesions that hold them together. We now report that epithelial tension at adherens junctions between migrating cells also increases due to an increase in RhoA-mediated junctional contractility. We find that active RhoA levels were stimulated by p114 RhoGEF at the junctions between migrating MCF-7 monolayers, and this was accompanied by increased levels of actomyosin and mechanical tension. Applying a strategy to restore active RhoA specifically at adherens junctions by manipulating its scaffold, anillin, we found that this junctional RhoA signal was necessary to stabilize junctional E-cadherin during epithelial migration and promoted orderly collective movement. We suggest that stabilization of E-cadherin by RhoA serves to increase cell-cell adhesion against the mechanical stresses of migration.
    Keywords:  Adherens junction; Contractility; E-cadherin; Epithelial migration; RhoA
    DOI:  https://doi.org/10.1242/jcs.258767
  16. EBioMedicine. 2021 Aug 05. pii: S2352-3964(21)00308-X. [Epub ahead of print]70 103515
    Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts.
    Jonathan Eintracht, Elizabeth Forsythe, Helen May-Simera, Mariya Moosajee.
      BACKGROUND: Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the 'obesity ciliopathies' due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies.METHODS: Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function.
    FINDINGS: mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts, suggesting rescue of ciliary function.
    INTERPRETATION: The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies.
    Keywords:  ALMS1; Amlexanox; Ataluren; BBS2; Ciliopathies; Nonsense suppression
    DOI:  https://doi.org/10.1016/j.ebiom.2021.103515
  17. Cell Death Discov. 2021 Aug 07. 7(1): 207
    Ursodeoxycholic acid suppresses the malignant progression of colorectal cancer through TGR5-YAP axis.
    Huan Zhang, Huanji Xu, Chenliang Zhang, Qiulin Tang, Feng Bi.
      The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.
    DOI:  https://doi.org/10.1038/s41420-021-00589-8
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