Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis

Neurogenetics ◽  
1997 ◽  
Vol 1 (1) ◽  
pp. 65-71 ◽  
Author(s):  
James S. Zu ◽  
Han-Xiang Deng ◽  
Terence P. Lo ◽  
Hiroshi Mitsumoto ◽  
Mohamed S. Ahmed ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Mutant Sod1 ◽  
Identification And Characterization ◽  
Lateral Sclerosis

Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients

Neurogenetics ◽  
2019 ◽  
Vol 20 (4) ◽  
pp. 197-208 ◽  
Author(s):  
Priyam Narain ◽  
Aditya K. Padhi ◽  
Upma Dave ◽  
Dibyakanti Mishra ◽  
Rohit Bhatia ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Identification And Characterization ◽  
Lateral Sclerosis

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 Characterization of the Properties of a Novel Mutation in VAPB in Familial Amyotrophic Lateral Sclerosis

2010 ◽  
Vol 285 (51) ◽  
pp. 40266-40281 ◽  
Author(s):  
Han-Jou Chen ◽  
Georgia Anagnostou ◽  
Andrea Chai ◽  
James Withers ◽  
Alex Morris ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Novel Mutation ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

scholarly journals Disulfide Bond Mediates Aggregation, Toxicity, and Ubiquitylation of Familial Amyotrophic Lateral Sclerosis-linked Mutant SOD1

2007 ◽  
Vol 282 (38) ◽  
pp. 28087-28095 ◽  
Author(s):  
Jun-ichi Niwa ◽  
Shin-ichi Yamada ◽  
Shinsuke Ishigaki ◽  
Jun Sone ◽  
Miho Takahashi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Neuron Death ◽  
Mutant Sod1 ◽  
Intermolecular Disulfide Bonds ◽  
High Molecular Weight Aggregate ◽  
Lateral Sclerosis

Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds. Here we show that a non-physiological intermolecular disulfide bond between cysteines at positions 6 and 111 of mutant SOD1 is important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity, all of which were dramatically reduced when the pertinent cysteines were replaced in mutant SOD1 expressed in Neuro-2a cells. Dorfin is a ubiquityl ligase that specifically binds familial ALS-linked mutant SOD1 and ubiquitylates it, thereby promoting its degradation. We found that Dorfin ubiquitylated mutant SOD1 by recognizing the Cys6- and Cys111-disulfide cross-linked form and targeted it for proteasomal degradation.

scholarly journals FAIM Opposes Aggregation of Mutant SOD1 That Typifies Some Forms of Familial Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 14 ◽  
Author(s):  
Hiroaki Kaku ◽  
Alexander V. Ludlow ◽  
Michael F. Gutknecht ◽  
Thomas L. Rothstein
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Mutant Sod1 ◽  
Lateral Sclerosis

scholarly journals Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis

2011 ◽  
Vol 118 (2) ◽  
pp. 266-280 ◽  
Author(s):  
Elisa Onesto ◽  
Paola Rusmini ◽  
Valeria Crippa ◽  
Nicola Ferri ◽  
Arianna Zito ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscle Cells ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Mutant Sod1 ◽  
Lateral Sclerosis
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