scholarly journals The Role of RPGR and Its Interacting Proteins in Ciliopathies

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Sarita Rani Patnaik ◽  
Rakesh Kotapati Raghupathy ◽  
Xun Zhang ◽  
David Mansfield ◽  
Xinhua Shu
Keyword(s):  
Retinitis Pigmentosa ◽  
Clinical Features ◽  
Protein Trafficking ◽  
Genetic Disorders ◽  
Interacting Proteins ◽  
Ciliary Protein ◽  
Retinal Disorders ◽  
Inherited Retinal Disorders ◽  
Insight Into

Ciliopathies encompass a group of genetic disorders characterized by defects in the formation, maintenance, or function of cilia. Retinitis pigmentosa (RP) is frequently one of the clinical features presented in diverse ciliopathies. RP is a heterogeneous group of inherited retinal disorders, characterized by the death of photoreceptors and affecting more than one million individuals worldwide. Theretinitis pigmentosa GTPase regulator(RPGR) gene is mutated in up to 20% of all RP patients. RPGR protein has different interacting partners to function in ciliary protein trafficking. In this review, we specifically focus on RPGR and its two interacting proteins: RPGRIP1 and RPGRIP1L. We summarize the function of the three proteins and highlight recent studies that provide insight into the cellular function of those proteins.

scholarly journals Novel Homozygous TULP1 and RPE65 Variants Underlies Recessive Retinitis Pigmentosa

2020 ◽  
Author(s):  
Amjad Khan ◽  
Xiao Bai ◽  
Muhammad Umair ◽  
Shirui Han ◽  
Xiaerbati Habulieti ◽  
...  
Keyword(s):  
Data Analysis ◽  
Retinitis Pigmentosa ◽  
Molecular Mechanisms ◽  
Mutation Screening ◽  
Missense Variant ◽  
Disease Phenotype ◽  
Whole Exome ◽  
Retinal Disorders ◽  
Pakistani Families ◽  
Inherited Retinal Disorders

Retinitis pigmentosa (RP) clinically and genetically heterogeneous group of inherited retinal disorders (IRD) that result in retinal degeneration. This study aimed to identify the genetic findings of patients with autosomal recessive retinitis pigmentosa (arRP). Whole exome sequencing (WES) was performed in two unrelated Pakistani families underlying arRP. Data analysis and mutation screening was performed for all the known RP genes following bi-directional Sanger sequencing to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. WES data analysis revealed a novel homozygous missense variant (c.1274T>C) in the in Tubby like Protein 1 (TULP1 NM_003322.6) gene in family 1 and a novel homozygous frameshift variant (c.351delC) in the retinoid isomerohydrolase 65 (RPE65 NM_000329.3) gene in family 2. The identified variants perfectly co-segregated with the disease phenotype within the families. Our results strongly suggest that mutations in TULP1 and RPE65 are responsible for the retinal phenotype in the affected individuals. These mutations will increase the mutation spectrum of these genes; furthermore, it will enhance our knowledge and understanding of the underlying molecular mechanisms of retinitis pigmentosa.

scholarly journals ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure

2018 ◽  
Vol 29 (13) ◽  
pp. 1590-1598 ◽  
Author(s):  
Abigail R. Moye ◽  
Ratnesh Singh ◽  
Victoria A. Kimler ◽  
Tanya L. Dilan ◽  
Daniella Munezero ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Outer Segment ◽  
Photoreceptor Cells ◽  
Visual Response ◽  
Photoreceptor Degeneration ◽  
Progressive Reduction ◽  
Ciliary Protein ◽  
Vertically Aligned ◽  
And Function

The outer segment (OS) of photoreceptor cells is an elaboration of a primary cilium with organized stacks of membranous disks that contain the proteins needed for phototransduction and vision. Though ciliary formation and function has been well characterized, little is known about the role of cilia in the development of photoreceptor OS. Nevertheless, progress has been made by studying mutations in ciliary proteins, which often result in malformed OSs and lead to blinding diseases. To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa. The KO mice display an early and progressive reduction in visual response. Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes. Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs. On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision.

scholarly journals Lipid Modifications in Cilia Biology

2019 ◽  
Vol 8 (7) ◽  
pp. 921 ◽  
Author(s):  
Kasturi Roy ◽  
Ethan P. Marin
Keyword(s):  
Protein Stability ◽  
Signaling Pathways ◽  
Protein Trafficking ◽  
Specific Protein ◽  
Signaling Cascades ◽  
Cellular Structures ◽  
Future Studies ◽  
Lipid Modifications ◽  
Ciliary Protein

Cilia are specialized cellular structures with distinctive roles in various signaling cascades. Ciliary proteins need to be trafficked to the cilium to function properly; however, it is not completely understood how these proteins are delivered to their final localization. In this review, we will focus on how different lipid modifications are important in ciliary protein trafficking and, consequently, regulation of signaling pathways. Lipid modifications can play a variety of roles, including tethering proteins to the membrane, aiding trafficking through facilitating interactions with transporter proteins, and regulating protein stability and abundance. Future studies focusing on the role of lipid modifications of ciliary proteins will help our understanding of how cilia maintain specific protein pools strictly connected to their functions.

Variability of FP-CIT PET Patterns Associated With Clinical Features of Multiple System Atrophy

Neurology ◽  
2021 ◽  
Vol 96 (12) ◽  
pp. e1663-e1671
Author(s):  
Reeree Lee ◽  
Jung Hwan Shin ◽  
Hongyoon Choi ◽  
Han-Joon Kim ◽  
Gi Jeong Cheon ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Clinical Features ◽  
Spatial Patterns ◽  
Disease Duration ◽  
Clinical Presentation ◽  
Principal Component ◽  
Specific Pattern ◽  
Underlying Pathophysiology ◽  
Insight Into

ObjectiveTo validate the role of the dopamine transporter (DAT) imaging as a biomarker in multiple system atrophy (MSA), we analyzed the association between spatial patterns of [18F]fluoro-propyl-carbomethoxy-iodophenyl-tropane ([18F]FP-CIT) PET and the clinical characteristics of MSA.MethodsSixty-five patients with MSA who underwent [18F]FP-CIT PET between 2009 and 2018 were retrospectively enrolled. To identify spatial patterns of [18F]FP-CIT PET, principal component (PC) analysis was used and correlated with the clinical presentation.ResultsOf the 65 patients, 42 presented with parkinsonian subtype of MSA, and 23 presented with cerebellar subtype of MSA (mean age 63.7 ± 9.3 years; disease duration, 1.8 ± 1.8 years). Each PC represents a specific pattern of degeneration: PC1 and PC2 were associated with the DAT binding of the entire putamen and the posterior putamen, respectively. PC3 was associated with increased [18F]FP-CIT uptake of the caudate and decreased uptake of the dorsal pons. PC2 was significantly correlated with the presence of parkinsonism (p = 5.34 × 10−5) and a positive levodopa response (p = 0.044), with age as a cofactor. PC3 was correlated with the presence of urinary incontinence (p = 0.036). Onset age was significantly correlated with both PC2 (R = 0.48, p = 5.0 × 10−5) and PC3 (R = −0.39, p = 0.0013).ConclusionsThe spatial pattern of DAT binding can reflect distinct clinical features of MSA and provides insight into the underlying pathophysiology of a broad spectrum of clinical features in MSA.

scholarly journals Neuroimaging of Narcolepsy and Primary Hypersomnias

2020 ◽  
Vol 26 (4) ◽  
pp. 310-327 ◽  
Author(s):  
Carlo Cavaliere ◽  
Mariachiara Longarzo ◽  
Stuart Fogel ◽  
Maria Engström ◽  
Andrea Soddu
Keyword(s):  
Sleep Disorders ◽  
Clinical Features ◽  
Neurological Disorders ◽  
Potential Role ◽  
Neural Basis ◽  
Subjective Assessments ◽  
Sleep Physiology ◽  
Idiopathic Hypersomnia ◽  
Insight Into

Advances in neuroimaging open up the possibility for new powerful tools to be developed that potentially can be applied to clinical populations to improve the diagnosis of neurological disorders, including sleep disorders. At present, the diagnosis of narcolepsy and primary hypersomnias is largely limited to subjective assessments and objective measurements of behavior and sleep physiology. In this review, we focus on recent neuroimaging findings that provide insight into the neural basis of narcolepsy and the primary hypersomnias Kleine-Levin syndrome and idiopathic hypersomnia. We describe the role of neuroimaging in confirming previous genetic, neurochemical, and neurophysiological findings and highlight studies that permit a greater understanding of the symptoms of these sleep disorders. We conclude by considering some of the remaining challenges to overcome, the existing knowledge gaps, and the potential role for neuroimaging in understanding the pathogenesis and clinical features of narcolepsy and primary hypersomnias.

scholarly journals Ciliary entry of KIF17 is dependent on its binding to the IFT-B complex via IFT46–IFT56 as well as on its nuclear localization signal

2017 ◽  
Vol 28 (5) ◽  
pp. 624-633 ◽  
Author(s):  
Teruki Funabashi ◽  
Yohei Katoh ◽  
Saki Michisaka ◽  
Masaya Terada ◽  
Maho Sugawa ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Protein Trafficking ◽  
Nuclear Localization Signal ◽  
Mammalian Cells ◽  
Permeability Barrier ◽  
Extracellular Signals ◽  
Ciliary Protein ◽  
Importin Α ◽  
Localization Signal

Cilia function as cellular antennae to sense and transduce extracellular signals. A number of proteins are specifically localized in cilia. Anterograde and retrograde ciliary protein trafficking are mediated by the IFT-B and IFT-A complexes in concert with kinesin-2 and dynein-2 motors, respectively. However, the role of KIF17, a homodimeric kinesin-2 protein, in protein trafficking has not been fully understood in vertebrate cilia. In this study, we demonstrated, by using the visible immunoprecipitation assay, that KIF17 interacts with the IFT46–IFT56 dimer in the IFT-B complex through its C-terminal sequence located immediately upstream of the nuclear localization signal (NLS). We then showed that KIF17 reaches the ciliary tip independently of its motor domain and requires IFT-B binding for its entry into cilia rather than for its intraciliary trafficking. We further showed that KIF17 ciliary entry depends not only on its binding to IFT-B but also on its NLS, to which importin α proteins bind. Taking the results together, we conclude that in mammalian cells, KIF17 is dispensable for ciliogenesis and IFT-B trafficking but requires IFT-B, as well as its NLS, for its ciliary entry across the permeability barrier located at the ciliary base.

scholarly journals Retinitis Pigmentosa Mutants Provide Insight into the Role of the N-terminal Cap in Rhodopsin Folding, Structure, and Function

2013 ◽  
Vol 288 (47) ◽  
pp. 33912-33926 ◽  
Author(s):  
Chikwado A. Opefi ◽  
Kieron South ◽  
Christopher A. Reynolds ◽  
Steven O. Smith ◽  
Philip J. Reeves
Keyword(s):  
Retinitis Pigmentosa ◽  
Structure And Function ◽  
Folding Structure ◽  
And Function ◽  
Insight Into

Role of molecular chaperones in steroid receptor action

2004 ◽  
Vol 40 ◽  
pp. 41-58 ◽  
Author(s):  
William B Pratt ◽  
Mario D Galigniana ◽  
Yoshihiro Morishima ◽  
Patrick J M Murphy
Keyword(s):  
Transcriptional Activation ◽  
Protein Trafficking ◽  
Steroid Receptors ◽  
Transcriptional Regulatory ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Receptor Action ◽  
Binding Cleft ◽  
Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

1992 ◽  
Vol 67 (01) ◽  
pp. 111-116 ◽  
Author(s):  
Marcel Levi ◽  
Jan Paul de Boer ◽  
Dorina Roem ◽  
Jan Wouter ten Cate ◽  
C Erik Hack
Keyword(s):  
Monoclonal Antibodies ◽  
Plasminogen Activator ◽  
Plasma Levels ◽  
Fold Increase ◽  
Fibrinolytic System ◽  
Plasminogen Activation ◽  
Plasminogen Activator Activity ◽  
Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

On Metaphysics and the Political: A Polemics of Reading Baudelaire in the 1930s

2019 ◽  
Vol 58 (2) ◽  
pp. 249-259
Author(s):  
Joseph Acquisto
Keyword(s):  
Twentieth Century ◽  
Political Crisis ◽  
The Political ◽  
Modern Poetry ◽  
Progressive Politics ◽  
The World ◽  
Relationship Of ◽  
The Relationship ◽  
Insight Into

This essay examines a polemic between two Baudelaire critics of the 1930s, Jean Cassou and Benjamin Fondane, which centered on the relationship of poetry to progressive politics and metaphysics. I argue that a return to Baudelaire's poetry can yield insight into what seems like an impasse in Cassou and Fondane. Baudelaire provides the possibility of realigning metaphysics and politics so that poetry has the potential to become the space in which we can begin to think the two of them together, as opposed to seeing them in unresolvable tension. Or rather, the tension that Baudelaire animates between the two allows us a new way of thinking about the role of esthetics in moments of political crisis. We can in some ways see Baudelaire as responding, avant la lettre, to two of his early twentieth-century readers who correctly perceived his work as the space that breathes a new urgency into the questions of how modern poetry relates to the world from which it springs and in which it intervenes.

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