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Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders.

Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders. Angew Chem Int Ed Engl. 2018 Apr 12;: Authors: Bunck DN, Atsavapranee B, Museth AK, VanderVelde D, Heath JR Abstract Amyotrophic lateral sclerosis, or Lou Gehrig's disease, is characterized by motor neuron death with average survival times of 2 - 5 years. One cause of this disease is the misfolding of superoxide dismutase 1 (SOD1), a protein whose stability and aggregation propensity are affected by point mutations spanning the protein. Here, we use an epitope-specific, high-throughput screen to identify peptides that both stabilize the native conformation of SOD1 as well as accelerate its folding by 2.5-fold. Ligands targeted to the electrostatic loop on the periphery of the protein tightened the non-metalated structure and accelerated its folding. This strategy may be useful for fundamental studies of protein energy landscapes as well as designing new classes of therapeutics. PMID: 29645329 [PubMed - as supplied by publisher]
Source: Angewandte Chemie - Category: Chemistry Authors: Tags: Angew Chem Int Ed Engl Source Type: research

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Authors: Agosta F, Spinelli EG, Filippi M Abstract INTRODUCTION: Several neuroimaging techniques have been used to define in vivo markers of pathological alterations underlying amyotrophic lateral sclerosis (ALS). Growing evidence supports the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) for the non-invasive detection of central nervous system involvement in patients with ALS. Areas covered: A comprehensive overview of structural and functional neuroimaging applications in ALS is provided, focusing on motor and extra-motor involvement in the brain and the spinal cord. Implications for...
Source: Expert Review of Neurotherapeutics - Category: Neurology Tags: Expert Rev Neurother Source Type: research
Abstract TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393 L and G294 V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only ...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
Muscle&Nerve, EarlyView.
Source: Muscle and Nerve - Category: Internal Medicine Authors: Source Type: research
Contributors : Wouter van Rheenen ; Frank P Diekstra ; Oliver Harschnitz ; Kristel R van Eijk ; Henk-Jan Westeneng ; Christiaan G Saris ; Ewout J Groen ; Michael A van Es ; Hylke M Blauw ; Paul W van Vught ; Jan H Veldink ; Leonard H van den BergSeries Type : Expression profiling by arrayOrganism : Homo sapiensTranscriptome-wide analysis of whole blood gene expression profiles of ALS patients, gender- and age-matched controls and patients diagnosed with diseases mimicking ALS at a tertiary referral center for motor neuron diseases.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research
Contributors : Wouter van Rheenen ; Frank P Diekstra ; Oliver Harschnitz ; Kristel R van Eijk ; Henk-Jan Westeneng ; Christiaan G Saris ; Ewout J Groen ; Michael A van Es ; Hylke M Blauw ; Paul W van Vught ; Jan H Veldink ; Leonard H van den BergSeries Type : Expression profiling by arrayOrganism : Homo sapiensTranscriptome-wide analysis of whole blood gene expression profiles of ALS patients, gender- and age-matched controls and patients diagnosed with diseases mimicking ALS at a tertiary referral center for motor neuron diseases.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and...
Source: BMC Neurology - Category: Neurology Authors: Tags: Research article Source Type: research
We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FαMN size and function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FαMN survival even in the mutant SOD1 background. These...
Source: Neuron - Category: Neuroscience Source Type: research
We reported a sporadic case of olanzapine-induced rapid-onset Type 2 diabetes with severe hyperglycemia.2 In our case, the patient was negative for anti-glutamic acid decarboxylase antibodies, and the discontinuation of olanzapine and careful insulin replacement regimen reversed diabetes. A common feature between these two cases is acute-onset severe hyperglycemia. The first presentation of diabetes associated with olanzapine might be diabetic ketoacidosis (DKA), requiring admission to an intensive care unit. Patients exposed to antipsychotics have approximately 10 times increased risk of DKA compared to the general popula...
Source: Innovations in Clinical Neuroscience - Category: Neuroscience Authors: Tags: Current Issue Letters to the Editor Source Type: research
The diagnosis of amyotrophic lateral sclerosis (ALS) requires (1) evidence for extensive upper and lower motor neuron dysfunction, (2) progressive course, and (3) exclusion of other causes of motor neuronal loss. So far, a number of diagnostic criteria for ALS have been proposed, such as El Escorial (1990), revised El Escorial (1998), Awaji (2008), and updated Awaji (2015). According to the frequent revision/proposal criteria, electrodiagnostic criteria for ALS are somewhat confusing. In these criteria, the body motor system are divided into 4 regions; cranial, cervical, thoracic, and lumbosacral, and evidence for upper an...
Source: Clinical Neurophysiology - Category: Neuroscience Authors: Source Type: research
We examined whether muscle ultrasonography is an effective diagnostic tool of amyotrophic lateral sclerosis (ALS). Analysis was performed in 17 patients with ALS or motor neuron disease. An Aplio XG ultrasonography device and a 7.5-MHz linear probe were used to observe 11 muscles for 20  s to determine the presence or absence of fasciculation. The overall fasciculation positive rate was 68.5%, and it was higher in the limbs.
Source: Clinical Neurophysiology - Category: Neuroscience Authors: Source Type: research
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