Aberrant association of misfolded SOD1 with Na + /K + ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS

Abstract Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na+/K+ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na+/K+ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na+/K+ATPase-α3 onto a 10 amino acid stretch that is unique to Na+/K+ATPase-α3 but not found in the closely related Na+/K+ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na+/K+ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na+/K+ATPase...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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AbstractIn acute gastroenteritis (AGE), identification of the infectious agent is important for patient management. Since symptoms do not reliably identify the agent, microbiological diagnostics are important. Conventional methods lack sensitivity and often take days. Multiplex PCR panels offer fast and sensitive alternatives. Our aim was to assess the performance of the new QIAstat Gastrointestinal Panel (GIP) detecting 24 different gastroenteric pathogens from stool in Cary-Blair transport medium (Adenovirus F 40/41, Astrovirus, Norovirus GI/GII, Rotavirus A, Sapovirus,Campylobacter spp.,Clostridium difficile,Plesiomonas...
Source: European Journal of Clinical Microbiology and Infectious Diseases - Category: Microbiology Source Type: research
ConclusionThis review shows that CAM may be useful for ALS treatment, but more evidence regarding the efficacy and molecular mechanisms is required to establish CAM as a good therapy for the treatment of ALS patients.
Source: Integrative Medicine Research - Category: Complementary Medicine Source Type: research
This study analyzed PCT and CRP levels of 214 pediatric patients with a median age of 8.5  years (0.4–17.8 years) undergoing allogeneic HSCT with respect to major TRAE.Results26 patients (12.1%) did not experience TRAE (control group), and 188 (87.9%) experienced median 2 (range 1 –4) TRAE. Median CRP and PCT were highly and significantly increased during sepsis/SIRS and bacteremia (17.24 mg/dl | 6.30 ng/ml;p 
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of a rapid course. In 25% of ALS sufferers, speech disorders occur as prodromal symptoms of the disease. Impaired communication affects physi...
Source: BMC Neurology - Category: Neurology Authors: Tags: Research article Source Type: research
Amyotrophic Lateral Sclerosis (ALS) is an incurable motor neuron (MN) disorder, characterized by degeneration of MNs leading to progressive paralysis and death within two to five years after diagnosis. Gene therapy is emerging as promising treatment option for patients affected by familial forms of ALS (fALS), representing 10% of all ALS cases. Taking advantage of viral vectors derived from Adeno-Associated Virus serotype 10 (AAV10) and the small nuclear RNA U7, we developed a gene therapy for SOD1-linked ALS (20% of fALS).
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Mir-17∼92 Confers Motor Neuron Subtype Differential Resistance to ALS-Associated Degeneration. Cell Stem Cell. 2019 May 21;: Authors: Tung YT, Peng KC, Chen YC, Yen YP, Chang M, Thams S, Chen JA Abstract Progressive degeneration of motor neurons (MNs) is the hallmark of amyotrophic lateral sclerosis (ALS). Limb-innervating lateral motor column MNs (LMC-MNs) seem to be particularly vulnerable and are among the first MNs affected in ALS. Here, we report association of this differential susceptibility with reduced expression of the mir-17∼92 cluster in LMC-MNs prior to disease onset. Reduced mir-...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research
Purpose of review Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS. Recent findings The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental...
Source: Current Opinion in Neurology - Category: Neurology Tags: MOTOR NEURON DISEASE: Edited by Jeremy Shefner and Shafeeq S. Ladha Source Type: research
In conclusion, we report a convenient and noninvasive ALS treatment method. Our results revealed a previously unrecognized role of IGF1 in p38 MAPK and the JNK-mediated pathway and its potential role as a therapeutic target for ALS. PMID: 29499331 [PubMed - as supplied by publisher]
Source: Brain Research Bulletin - Category: Neurology Authors: Tags: Brain Res Bull Source Type: research
Our research is devoted to the identification of efficient strategies to target the central nervous system (CNS) and to the development of novel therapies for motor neuron disorders. In particular, using the unique therapeutic potential of self-complementary adeno-associated virus (AAV) vectors, we recently elaborated a new gene therapy strategy for a genetic form of Amyotrophic Lateral Sclerosis (ALS), a lethal disease with limited therapeutic options. Approximately 20% of familial ALS cases are caused by mutations in the Superoxide Dismutase 1 (SOD1) gene and toxic gain of function of the mutant protein.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Conclusions:Identification of the mechanisms of neuronal differential vulnerability may lead to development of new therapeutic strategies that prevent the progressive neurodegeneration in MN diseases.Study Supported by: Cariplo Foundation to SC (2012-0513), Thierry Latran Foundation to SC and EH, JPND; 529-2014-7500 to SC and EH; ARISLA to SC.Disclosure: Dr. Nizzardo has nothing to disclose. Dr. Rizzo has nothing to disclose. Dr. Taiana has nothing to disclose. Dr. Allodi has nothing to disclose. Dr. Aguila Benitez has nothing to disclose. Dr. Nijssen has nothing to disclose. Dr. Ulzi has nothing to disclose. Dr. Melzi has...
Source: Neurology - Category: Neurology Authors: Tags: Neuromuscular and Clinical Neurophysiology (EMG): Motor Neuron Disease I Source Type: research
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