scholarly journals Molecular insights into the human CLC-7/Ostm1 transporter

2020 ◽  
Vol 6 (33) ◽  
pp. eabb4747 ◽  
Author(s):  
Sensen Zhang ◽  
Yang Liu ◽  
Bing Zhang ◽  
Jun Zhou ◽  
Tianyu Li ◽  
...  
Keyword(s):  
Complex Structure ◽  
Chloride Ions ◽  
Amino Terminus ◽  
Lysosomal Storage ◽  
Domain Interaction ◽  
Cryo Electron Microscopy ◽  
Cbs Domains ◽  
And Control ◽  
Kinetics Of ◽  
Storage Disorders

CLC family proteins translocate chloride ions across cell membranes to maintain the membrane potential, regulate the transepithelial Cl− transport, and control the intravesicular pH among different organelles. CLC-7/Ostm1 is an electrogenic Cl−/H+ antiporter that mainly resides in lysosomes and osteoclast ruffled membranes. Mutations in human CLC-7/Ostm1 lead to lysosomal storage disorders and severe osteopetrosis. Here, we present the cryo–electron microscopy (cryo-EM) structure of the human CLC-7/Ostm1 complex and reveal that the highly glycosylated Ostm1 functions like a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane. Our complex structure reveals a functionally crucial domain interface between the amino terminus, TMD, and CBS domains of CLC-7. Structural analyses and electrophysiology studies suggest that the domain interaction interfaces affect the slow gating kinetics of CLC-7/Ostm1. Thus, our study deepens understanding of CLC-7/Ostm1 transporter and provides insights into the molecular basis of the disease-related mutations.

Investigation of irradiation-induced nucleation processes in silicon and germanium

1995 ◽  
Vol 53 ◽  
pp. 224-225
Author(s):  
Harry A. Atwater ◽  
C.M. Yang ◽  
K.V. Shcheglov
Keyword(s):  
Room Temperature ◽  
Crystal Size ◽  
Initial Distribution ◽  
Engineering Control ◽  
Size Evolution ◽  
Silicon And Germanium ◽  
Ge Quantum Dot ◽  
And Control ◽  
Germanium Quantum Dots ◽  
Kinetics Of

Studies of the initial stages of nucleation of silicon and germanium have yielded insights that point the way to achievement of engineering control over crystal size evolution at the nanometer scale. In addition to their importance in understanding fundamental issues in nucleation, these studies are relevant to efforts to (i) control the size distributions of silicon and germanium “quantum dots𠇍, which will in turn enable control of the optical properties of these materials, (ii) and control the kinetics of crystallization of amorphous silicon and germanium films on amorphous insulating substrates so as to, e.g., produce crystalline grains of essentially arbitrary size.Ge quantum dot nanocrystals with average sizes between 2 nm and 9 nm were formed by room temperature ion implantation into SiO2, followed by precipitation during thermal anneals at temperatures between 30°C and 1200°C[1]. Surprisingly, it was found that Ge nanocrystal nucleation occurs at room temperature as shown in Fig. 1, and that subsequent microstructural evolution occurred via coarsening of the initial distribution.

Computer processing of high-resolution images of periodic specimens

1986 ◽  
Vol 44 ◽  
pp. 2-5
Author(s):  
W. Chiu ◽  
M.F. Schmid ◽  
T.-W. Jeng
Keyword(s):  
High Resolution ◽  
Fourier Transforms ◽  
Complex Structure ◽  
Distribution Functions ◽  
Multiple Image ◽  
Cryo Electron Microscopy ◽  
Structure Factors ◽  
Unit Cells ◽  
High Resolution Images ◽  
Phase Probability Distribution

Cryo-electron microscopy has been developed to the point where one can image thin protein crystals to 3.5 Å resolution. In our study of the crotoxin complex crystal, we can confirm this structural resolution from optical diffractograms of the low dose images. To retrieve high resolution phases from images, we have to include as many unit cells as possible in order to detect the weak signals in the Fourier transforms of the image. Hayward and Stroud proposed to superimpose multiple image areas by combining phase probability distribution functions for each reflection. The reliability of their phase determination was evaluated in terms of a crystallographic “figure of merit”. Grant and co-workers used a different procedure to enhance the signals from multiple image areas by vector summation of the complex structure factors in reciprocal space.

scholarly journals Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

2021 ◽  
Author(s):  
Daniel Erskine ◽  
David Koss ◽  
Viktor I. Korolchuk ◽  
Tiago F. Outeiro ◽  
Johannes Attems ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Mitochondrial Diseases ◽  
Model Systems ◽  
Lipid Homeostasis ◽  
Lysosomal Storage ◽  
Iron Storage ◽  
Monogenic Disorders ◽  
Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

scholarly journals Potential resistance to SARS-CoV-2 infection in lysosomal storage disorders

2021 ◽  
Author(s):  
Maurizio Pieroni ◽  
Federico Pieruzzi ◽  
Renzo Mignani ◽  
Francesca Graziani ◽  
Iacopo Olivotto ◽  
...  
Keyword(s):  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria De Risi ◽  
Michele Tufano ◽  
Filomena Grazia Alvino ◽  
Maria Grazia Ferraro ◽  
Giulia Torromino ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Sch 23390 ◽  
Lysosomal Storage Disorders ◽  
Dopamine Neurons ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Cellular Models ◽  
Mps Ii ◽  
Mps Iiia ◽  
Storage Disorders

AbstractLysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Lysosomal Storage Disorders as an Etiology of Nonimmune Hydrops Fetalis: A Systematic Review

2021 ◽  
Author(s):  
Neel S. Iyer ◽  
Alexis C. Gimovsky ◽  
Carlos R. Ferreira ◽  
Elizabeth J. Critchlow ◽  
Huda B. Al‐kouatly
Keyword(s):  
Systematic Review ◽  
Lysosomal Storage Disorders ◽  
Hydrops Fetalis ◽  
Lysosomal Storage ◽  
Nonimmune Hydrops ◽  
Storage Disorders

scholarly journals A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Atul Mehta ◽  
Uma Ramaswami ◽  
Joseph Muenzer ◽  
Roberto Giugliani ◽  
Kurt Ullrich ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Clinical Manifestations ◽  
Lysosomal Storage Disorders ◽  
Expert Committee ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Access Program ◽  
Storage Disorders

Abstract Background Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs. Methods The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company. Results As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year. Conclusions The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

scholarly journals Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology

2016 ◽  
Vol 311 (5) ◽  
pp. F1015-F1024 ◽  
Author(s):  
Ester M. Pereira ◽  
Anatália Labilloy ◽  
Megan L. Eshbach ◽  
Ankita Roy ◽  
Arohan R. Subramanya ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Human Kidney ◽  
Premature Death ◽  
Antibody Array ◽  
Cell Models ◽  
Lysosomal Storage ◽  
Protein Levels ◽  
Gla Gene ◽  
Fabry Nephropathy ◽  
And Control

Fabry nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD), a rare X-linked lysosomal storage disorder. Gb3, the main substrate of α-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD.

Sign in / Sign up

Export Citation Format

Share Document