Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosisassociated SOD1 mutations

Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
Journal of Neurochemistry (Impact Factor: 4.28). 12/2008; 108(3):578-90. DOI: 10.1111/j.1471-4159.2008.05799.x
Source: PubMed


Mutations in Cu, Zn-superoxide dismutase 1 (SOD1) are associated with degeneration of motor neurons in the disease, familial amyotrophic lateral sclerosis. Intracellular protein inclusions containing mutant SOD1 (mSOD1) are associated with disease but it is unclear whether they are neuroprotective or cytotoxic. We report here that the formation of mSOD1 inclusions in a motor neuron-like cell line (NSC-34) strongly correlates with apoptosis via the mitochondrial death pathway. Applying confocal microscopic analyses, we observed changes in nuclear morphology and activation of caspase 3 specifically in cells expressing mSOD1 A4V or G85R inclusions. Furthermore, markers of mitochondrial apoptosis (activation and recruitment of Bax, and cytochrome c redistribution) were observed in 30% of cells bearing mSOD1 inclusions but not in cells expressing dispersed SOD1. In the presence of additional apoptotic challenges (staurosporine, etoposide, and hydrogen peroxide), cells bearing mSOD1 inclusions were susceptible to further apoptosis suggesting they were in a pro-apoptotic state, thus confirming that inclusions are linked to toxicity. Surprisingly, cells displaying dispersed SOD1 [both wildtype (WT) and mutant] were protected against apoptosis upstream of mitochondrial apoptotic signaling, induced by all agents tested. This protection against apoptosis was unrelated to SOD1 enzymatic activity because the G85R that lacks enzymatic function protected cells similarly to both WT SOD1 and A4V that possesses WT-like activity. These findings demonstrate new aspects of SOD1 in relation to cellular viability; specifically, mSOD1 can be either neuroprotective or cytotoxic depending on its aggregation state.

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Available from: Phillip Nagley, Dec 06, 2014
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    • "Activated caspase 3 , Bax and cytochrome c in cells bearing mutant SOD1 inclusions but not in cells expressing dispersed SOD1 . Soo et al . , 2009 HEK293 , SH - SY5Y SOD1 G93A Mutant SOD1 induces mitochondrial morphological changes and compromises mitochondrial membrane integrity leading to release of cytochrome C only in the presence of Bcl - 2 . Pedrini et al . , 2010 NSC - 34 Tg mice SOD1 G93A Induced Bcl2 - A1 expression via the AP1 transcription factor in motor neuronal cells"
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