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Acylation of SOD1 Provides Tool to determine if Mitochondrial Aggregation of SOD1 is Main Driver of ALS
Author(s) -
Banks Courtney,
Rodriguez Nathan,
Gashler Kyle,
Bikman Benjamin,
Andersen Joshua
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb167
Subject(s) - sod1 , mitochondrion , mutant , chemistry , cytosol , microbiology and biotechnology , biochemistry , biology , gene , enzyme
Most cases of ALS are sporadic but about 10% are familial (referred to as fALS), caused by mutations in a few known genes, including the ROS‐scavenging enzyme superoxide dismutase Cu/Zn (SOD1). These fALS‐linked mutations in SOD1 have no consistent effect on SOD1 ROS‐scavenging but rather are thought to cause a poorly understood toxic gain‐of‐function, believed by some groups to be an aggregation of mutant SOD1 in mitochondria that leads to neuronal death. However, the link between SOD1 mitochondrial aggregation and ALS is based on correlative data and has yet to be proven experimentally. Our preliminary experiments identified a novel mode of post‐translational SOD1 regulation by acylation (both acetylation and succinylation) at lysine 123 (K123). We observed that while acyl‐mimicking SOD1 mutants, K123E and K123Q, do not alter SOD1's ability to dimerize or scavenge ROS, they do abolish SOD1 mitochondrial localization even when combined with the fALS‐causing G93A mutation that is known to aggregate in the mitochondria. We also found that the acyl‐mimicking mutants of SOD1 abolish SOD1's ability to suppress respiration. In yeast, SOD1 is thought to suppress respiration in the cytosol through stabilization of casein kinase‐γ1 and the WNT pathway. However, the fact that the acyl‐mimicking mutants of SOD1 do not import into the mitochondria and also cannot suppress respiration suggests that SOD1's anti‐respiratory effect may be linked to SOD1's accumulation in mitochondria. We are now using the acyl‐mimicking SOD1 mutants as tools to determine if mitochondrial aggregation of mutant SOD1 is the main driver of ALS and if SOD1 mitochondrial localization is necessary for its anti‐respiratory activity. Support or Funding Information Simmons Center for Cancer Research, BYU Internal Funding