Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria.
Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis. We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord. We also demonstrate that in mice and humans, Bcl-2 binds to high molecular weight SDS-resistant mutant SOD1 containing aggregates that are present in mitochondria from spinal cord but not liver. These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein.
Pasinelli
Piera
P
Day Laboratory for Neuromuscular Research, Department of Neurology, Harvard Medical School, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA. ppasinelli@partners.org
Belford
Mary Elizabeth
ME
Lennon
Niall
N
Bacskai
Brian J
BJ
Hyman
Bradley T
BT
Trotti
Davide
D
Brown
Robert H
RH
D000818:Animals; D000870:Anterior Horn Cells / Q000201:enzymology / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000072105:Superoxide Dismutase-1
D046911:Macromolecular Substances; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1