scholarly journals Late Onset Death of Motor Neurons in Mice Overexpressing Wild-Type Peripherin

1999 ◽  
Vol 147 (3) ◽  
pp. 531-544 ◽  
Author(s):  
Jean-Martin Beaulieu ◽  
Minh Dang Nguyen ◽  
Jean-Pierre Julien
Keyword(s):  
Motor Neurons ◽  
Late Onset ◽  
Protein A ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Mutant Form ◽  
Wild Type ◽  
Neurofilament Light ◽  
Spinal Motor Neurons ◽  
Sporadic Als ◽  
Selective Death

Peripherin, a type III intermediate filament (IF) protein, upregulated by injury and inflammatory cytokines, is a component of IF inclusion bodies associated with degenerating motor neurons in sporadic amyotrophic lateral sclerosis (ALS). We report here that sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging. Remarkably, the onset of peripherin-mediated disease was precipitated by a deficiency of neurofilament light (NF-L) protein, a phenomenon associated with sporadic ALS. In NF-L null mice, the overexpression of peripherin led to early- onset formation of IF inclusions and to the selective death of spinal motor neurons at 6 mo of age. We also report the formation of similar peripherin inclusions in presymptomatic transgenic mice expressing a mutant form of superoxide dismutase linked to ALS. Taken together, these results suggest that IF inclusions containing peripherin may play a contributory role in motor neuron disease.

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

scholarly journals Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model

2022 ◽  
Vol 5 (4) ◽  
pp. e202101193
Author(s):  
Megumi Akamatsu ◽  
Takenari Yamashita ◽  
Sayaka Teramoto ◽  
Zhen Huang ◽  
Janet Lynch ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Motor Neurons ◽  
Ampa Receptors ◽  
Motor Dysfunction ◽  
Rna Aptamers ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Efficacy And Safety ◽  
Intracerebroventricular Infusion ◽  
Sporadic Als ◽  
Als Patients

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor–mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

scholarly journals Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes

2019 ◽  
Vol 28 (16) ◽  
pp. 2799-2810 ◽  
Author(s):  
Ching-On Wong ◽  
Kartik Venkatachalam
Keyword(s):  
Cell Adhesion ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Data Sets ◽  
Spinal Motor Neurons ◽  
Expression Of Genes ◽  
Sporadic Als ◽  
Elevated Expression ◽  
Induced Pluripotent ◽  
Als Patients

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the continuum, we detected diminished expression of genes repressed by quiescence-promoting E2F4/DREAM complex. Proteins whose abundance was significantly altered in C9-ALS neurons faithfully recapitulated the transcriptional aberrations. Importantly, patterns of gene expression in spinal motor neurons dissected from C9-ALS or sporadic ALS patients were highly concordant with each other and with the C9-ALS iPSC neurons. In contrast, motor neurons from patients with mutations in SOD1 exhibited dramatically different signatures. Elevated expression of gene sets such as ECM and cell adhesion genes occurs in C9 and sporadic ALS but not SOD1-ALS. These analyses indicate that despite the similarities in outward manifestations, transcriptional and proteomic signatures in ALS motor neurons can vary significantly depending on the identity of the causal mutations.

Otolaryngologist’s role in the diagnosis of amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (2) ◽  
pp. e234504
Author(s):  
Joana Borges Costa ◽  
Diogo Pereira ◽  
Delfim Duarte ◽  
Miguel Viana
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Clinical Presentation ◽  
Late Onset ◽  
History Of ◽  
Dysarthric Speech ◽  
Selective Death ◽  
Hypernasal Voice ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and late-onset fatal neurodegenerative disease characterised by selective death of motor neurons. The aetiology of ALS is still unknown and it is extremely heterogeneous in genetics and clinical presentation, being the respiratory failure the usual cause of death. We describe a case of a 61-year-old male patient referred to the otolaryngology consultation for a 6-month history of progressive solid dysphagia and dysphonia. The patient presented several voice alterations such as a dysarthric speech with hypernasal voice which evoked the hypothesis of a neuromuscular disease. That patient was observed by a neurologist and was submitted to an electromyography that confirmed the ALS diagnosis. This case highlights the key role of otolaryngologists in the diagnosis of ALS, in a way that many patients with a bulbar ALS form are initially studied by an otolaryngologist.

Predicting disease specific spinal motor neurons and glia in sporadic ALS

2019 ◽  
Vol 130 ◽  
pp. 104523 ◽  
Author(s):  
Fabien Dachet ◽  
Jiangou Liu ◽  
John Ravits ◽  
Fei Song
Keyword(s):  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Sporadic Als ◽  
Disease Specific

Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis

2005 ◽  
Vol 57 (2) ◽  
pp. 236-251 ◽  
Author(s):  
Yue-Mei Jiang ◽  
Masahiko Yamamoto ◽  
Yasushi Kobayashi ◽  
Tsuyoshi Yoshihara ◽  
Yideng Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amyotrophic Lateral Sclerosis ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Motor Neurons ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Lateral Sclerosis

scholarly journals Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

2020 ◽  
Author(s):  
Edward Pokrishevsky ◽  
Michèle G. DuVal ◽  
Luke McAlary ◽  
Sarah Louadi ◽  
Silvia Pozzi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Inclusion Bodies ◽  
Dna Binding Protein ◽  
Effector Proteins ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Reporter Protein ◽  
Sporadic Als ◽  
Tryptophan Residues ◽  
Lateral Sclerosis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.

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