scholarly journals Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability

2013 ◽  
Vol 109 (11) ◽  
pp. 2803-2814 ◽  
Author(s):  
Elsa Fritz ◽  
Pamela Izaurieta ◽  
Alexandra Weiss ◽  
Franco R. Mir ◽  
Patricio Rojas ◽  
...  
Keyword(s):  
Calcium Transients ◽  
Repetitive Firing ◽  
Critical Element ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Site Of Action ◽  
Inward Currents ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1G93A) increases persistent sodium inward currents (PCNa), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Nav) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1G93A. These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1G93A on motoneurons is increased excitability, an observation with direct implications for therapy of ALS.

scholarly journals The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

2019 ◽  
Vol 52 ◽  
Author(s):  
Gareth S. A. Wright ◽  
Svetlana V. Antonyuk ◽  
S. Samar Hasnain
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Structural Integrity ◽  
Superoxide Dismutase 1 ◽  
Post Translational Modifications ◽  
Mutant Sod1 ◽  
Therapeutic Outcomes ◽  
The Many ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractFew proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

scholarly journals Induction of Protective Immunity by Vaccination With Wild-Type Apo Superoxide Dismutase 1 in Mutant SOD1 Transgenic Mice

2010 ◽  
Vol 69 (10) ◽  
pp. 1044-1056 ◽  
Author(s):  
Shigeko Takeuchi ◽  
Noriko Fujiwara ◽  
Akemi Ido ◽  
Miki Oono ◽  
Yuki Takeuchi ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Transgenic Mice ◽  
Protective Immunity ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Mutant Sod1

scholarly journals Oxidation of the Tryptophan 32 Residue of Human Superoxide Dismutase 1 Caused by Its Bicarbonate-dependent Peroxidase Activity Triggers the Non-amyloid Aggregation of the Enzyme

2014 ◽  
Vol 289 (44) ◽  
pp. 30690-30701 ◽  
Author(s):  
Fernando R. Coelho ◽  
Asif Iqbal ◽  
Edlaine Linares ◽  
Daniel F. Silva ◽  
Filipe S. Lima ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Peroxidase Activity ◽  
Oxidation Products ◽  
Superoxide Dismutase 1 ◽  
Amyloid Aggregation ◽  
Post Translational Modifications ◽  
Covalent Dimer ◽  
Als Patients ◽  
Lateral Sclerosis

The role of oxidative post-translational modifications of human superoxide dismutase 1 (hSOD1) in the amyotrophic lateral sclerosis (ALS) pathology is an attractive hypothesis to explore based on several lines of evidence. Among them, the remarkable stability of hSOD1WT and several of its ALS-associated mutants suggests that hSOD1 oxidation may precede its conversion to the unfolded and aggregated forms found in ALS patients. The bicarbonate-dependent peroxidase activity of hSOD1 causes oxidation of its own solvent-exposed Trp32 residue. The resulting products are apparently different from those produced in the absence of bicarbonate and are most likely specific for simian SOD1s, which contain the Trp32 residue. The aims of this work were to examine whether the bicarbonate-dependent peroxidase activity of hSOD1 (hSOD1WT and hSOD1G93A mutant) triggers aggregation of the enzyme and to comprehend the role of the Trp32 residue in the process. The results showed that Trp32 residues of both enzymes are oxidized to a similar extent to hSOD1-derived tryptophanyl radicals. These radicals decayed to hSOD1-N-formylkynurenine and hSOD1-kynurenine or to a hSOD1 covalent dimer cross-linked by a ditryptophan bond, causing hSOD1 unfolding, oligomerization, and non-amyloid aggregation. The latter process was inhibited by tempol, which recombines with the hSOD1-derived tryptophanyl radical, and did not occur in the absence of bicarbonate or with enzymes that lack the Trp32 residue (bovine SOD1 and hSOD1W32F mutant). The results support a role for the oxidation products of the hSOD1-Trp32 residue, particularly the covalent dimer, in triggering the non-amyloid aggregation of hSOD1.

scholarly journals Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution

2005 ◽  
Vol 280 (43) ◽  
pp. 35815-35821 ◽  
Author(s):  
Lucia Banci ◽  
Ivano Bertini ◽  
Nicola D'Amelio ◽  
Elena Gaggelli ◽  
Elisa Libralesso ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Copper Zinc Superoxide Dismutase ◽  
Intermolecular Contacts ◽  
Nmr Methods ◽  
The Individual ◽  
Lateral Sclerosis

S134N copper-zinc superoxide dismutase (SOD1) is one of the many mutant SOD1 proteins known to cause familial amyotrophic lateral sclerosis. Earlier studies demonstrated that partially metal-deficient S134N SOD1 crystallized in filament-like arrays with abnormal contacts between the individual protein molecules. Because protein aggregation is implicated in SOD1-linked familial amyotrophic lateral sclerosis, abnormal intermolecular interactions between mutant SOD1 proteins could be relevant to the mechanism of pathogenesis in the disease. We have therefore applied NMR methods to ascertain whether abnormal contacts also form between S134N SOD1 molecules in solution and whether Cys-6 or Cys-111 plays any role in the aggregation. Our studies demonstrate that the behavior of fully metallated S134N SOD1 is dramatically different from that of fully metallated wild type SOD1 with a region of subnanosecond mobility located close to the site of the mutation. Such a high degree of mobility is usually seen only in the apo form of wild type SOD1, because binding of zinc to the zinc site normally immobilizes that region. In addition, concentration-dependent chemical shift differences were observed for S134N SOD1 that were not observed for wild type SOD1, indicative of abnormal intermolecular contacts in solution. We have here also established that the two free cysteines (6 and 111) do not play a role in this behavior.

scholarly journals A diacidic motif determines unconventional secretion of wild-type and ALS-linked mutant SOD1

2017 ◽  
Vol 216 (9) ◽  
pp. 2691-2700 ◽  
Author(s):  
David Cruz-Garcia ◽  
Nathalie Brouwers ◽  
Juan M. Duran ◽  
Gabriel Mora ◽  
Amy J. Curwin ◽  
...  
Keyword(s):  
Signal Sequence ◽  
Nutrient Starvation ◽  
Mutant Form ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Cytoplasmic Proteins ◽  
Unconventional Secretion ◽  
Small Pool ◽  
Human Sod1 ◽  
Lateral Sclerosis

The nutrient starvation-specific unconventional secretion of Acb1 in Saccharomyces cerevisiae requires ESCRT-I, -II, and -III and Grh1. In this study, we report that another signal sequence lacking cytoplasmic protein, superoxide dismutase 1 (SOD1), and its mutant form linked to amyotrophic lateral sclerosis (ALS), is also secreted by yeast upon nutrient starvation in a Grh1- and ESCRT-I–, -II–, and -III–dependent process. Our analyses reveal that a conserved diacidic motif (Asp-Glu) in these proteins is necessary for their export. Importantly, secretion of wild-type human SOD1 and the ALS-linked mutant in human cells also require the diacidic residues. Altogether, these findings reveal information encoded within the cytoplasmic proteins required for their unconventional secretion and provide a means to unravel the significance of the cytoplasmic versus the secreted form of mutant SOD1 in the pathology of ALS. We also propose how cells, based on a signal-induced change in cytoplasmic physiology, select a small pool of a subset of cytoplasmic proteins for unconventional secretion.

scholarly journals Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study

2020 ◽  
Vol 21 (18) ◽  
pp. 6807
Author(s):  
Emilien Bernard ◽  
Antoine Pegat ◽  
Juliette Svahn ◽  
Françoise Bouhour ◽  
Pascal Leblanc ◽  
...  
Keyword(s):  
Superoxide Dismutase 1 ◽  
Sod1 Gene ◽  
Copper Zinc Superoxide Dismutase ◽  
Pathogenic Variants ◽  
Zinc Superoxide Dismutase ◽  
Sporadic Als ◽  
Copper Zinc ◽  
Molecular Landscape ◽  
Als Patients ◽  
Lateral Sclerosis

Mutations in the copper zinc superoxide dismutase 1 (SOD1) gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all SOD1 pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described H81Y and D126N mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of SOD1 gene in familial and sporadic ALS.

Early Excitability Changes in Lumbar Motoneurons of Transgenic SOD1G85R and SOD1G93A-Low Mice

2009 ◽  
Vol 102 (6) ◽  
pp. 3627-3642 ◽  
Author(s):  
Arnaud Pambo-Pambo ◽  
Jacques Durand ◽  
Jean-Patrick Gueritaud
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Wild Type ◽  
Persistent Inward Currents ◽  
Current Pulses ◽  
Inward Currents ◽  
Recording Conditions ◽  
Mutant Lines ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

This work characterizes the properties of wild-type (WT) mouse motoneurons in the second postnatal week and compares these at the same age and in the same conditions to those of two different SOD1 mutant lines used as models of human amyotrophic lateral sclerosis (ALS), the SOD1G93A low expressor line and SOD1G85R line, to describe any changes in the functional properties of mutant motoneurons (Mns) that may be related to the pathogenesis of human ALS. We show that very early changes in excitability occur in SOD1 mutant Mns that have different properties from those of WT animals. The SOD1G93A-Low low expressor line displays specific differences that are not found in other mutant lines including a more depolarized membrane potential, larger spike width, and slower spike rise slope. With current pulses SOD1G93A-Low were hyperexcitable, but both mutants had a lower gain with current ramps stimulation. Changes in the threshold and intensities of Na+ and Ca2+ persistent inward currents were also observed. Low expressor mutants show reduced total persistant inward currents compared with WT motoneurons in the same recording conditions and give arguments toward modifications of the balance between Na+ and Ca2+ persistent inward currents. During the second week postnatal, SOD1G93A-Low lumbar motoneurons appear more immature than those of SOD1G85R compared with WT and we propose that different time course of the disease, possibly linked with different toxic properties of the mutated protein in each model, may explain the discrepancies between excitability changes described in the different models.

scholarly journals ALS-linked SOD1 Mutants Enhance Outgrowth, Branching, and the Formation of Actin-Based Structures in Adult Motor Neurons

2018 ◽  
Author(s):  
Zachary Osking ◽  
Jacob I. Ayers ◽  
Ryan Hildebrandt ◽  
Kristen Skruber ◽  
Hilda Brown ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Expression Profiling ◽  
Growth Cones ◽  
Therapeutic Strategies ◽  
Axonal Outgrowth ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Dendritic Branching ◽  
Lateral Sclerosis ◽  
Cells Cultured

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by motor neuron cell death. However, not all motor neurons are equally susceptible. Most of what we know about the surviving motor neurons comes from gene expression profiling, less is known about their functional traits. We found that resistant motor neurons cultured from SOD1 ALS mouse models have enhanced axonal outgrowth and dendritic branching. They also have an increase in the number and size of actin-based structures like growth cones and filopodia. These phenotypes occur in cells cultured from presymptomatic mice and mutant SOD1 models that do not develop ALS, but not in embryonic motor neurons. Enhanced outgrowth and upregulation of filopodia can be induced in wild-type adult cells by expressing mutant SOD1. These results demonstrate that mutant SOD1 can enhance the regenerative capability of ALS resistant motor neurons. Capitalizing on this mechanism could lead to new therapeutic strategies.

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