Human Cu/Zn Superoxide Dismutase (SOD1) Overexpression in Mice Causes Mitochondrial Vacuolization, Axonal Degeneration, and Premature Motoneuron Death and Accelerates Motoneuron Disease in Mice Expressing a Familial Amyotrophic Lateral Sclerosis Mutant SOD1

2000 ◽  
Vol 7 (6) ◽  
pp. 623-643 ◽  
Author(s):  
Dick Jaarsma ◽  
Elize D. Haasdijk ◽  
J.A.C. Grashorn ◽  
Richard Hawkins ◽  
Wim van Duijn ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Axonal Degeneration ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Motoneuron Disease ◽  
Mutant Sod1 ◽  
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.

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