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

Kai Ying Soo, Julie D Atkin, Malcolm Kenneth Horne, Phillip Nagley

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26 Citations (Scopus)

Abstract

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 are associated with disease but it is unclear whether they are neuroprotective or cytotoxic. We report here that the formation of mutant SOD1 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 mutant SOD1 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 mutant SOD1 inclusions but not in cells expressing dispersed SOD1. In the presence of additional apoptotic challenges (staurosporine, etoposide and hydrogen peroxide), cells bearing mutant SOD1 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 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 wildtype SOD1 and A4V that possesses wildtype-like activity. These findings demonstrate new aspects of SOD1 in relation to cellular viability; specifically, mutant SOD1 can be either neuroprotective or cytotoxic depending on its aggregation state.
Original languageEnglish
Pages (from-to)578 - 590
Number of pages12
JournalJournal of Neurochemistry
Volume108
Publication statusPublished - 2009

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