Impaired Extracellular Secretion of Mutant Superoxide Dismutase 1 Associates with Neurotoxicity in Familial Amyotrophic Lateral Sclerosis

• DOI: 10.1523/jneurosci.4253-04.2005
• Publication Date: 2005-01-05T18:53:19Z
• Authors: Bradley J. Turner; Julie D. Atkin; Manal A. Farg; Da Wei Zang; Alan Rembach; Elizabeth C. Lopes; Justin D. Patch; Andrew F. Hill; Surindar S. Cheema
• Keywords: Brefeldin A; Neurotoxicity

Mutations in the intracellular metalloenzyme superoxide dismutase 1 (SOD1) are linked to neurotoxicity familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism. Golgi fragmentation and endoplasmic reticulum stress early hallmarks of spinal motor neuron pathology transgenic mice overexpressing mutant SOD1, suggesting that dysfunction neuronal secretory pathway may contribute ALS pathogenesis. We therefore proposed SOD1 directly engages modulates based on recent evidence secretion diverse human cell lines. Here, we demonstrate a fraction active endogenous is secreted NSC-34 neuron-like cells via brefeldin-A (BFA)-sensitive pathway. Expression enhanced green fluorescent protein-tagged (hSOD1-EGFP) induced frequent cytoplasmic inclusions protein insolubility correlated with toxicity. In contrast, transfection non-neuronal COS-7 resulted hSOD1-EGFP inclusions, oligomerization, without detectable Importantly, impaired was common all 10 mutants tested relative wild-type cells. Treatment BFA inhibited pronounced BFA-induced toxicity Extracellular targeting SOD3 signal peptide fusion attenuated inclusion formation The effect elevated extracellular then evaluated rat model ALS. Chronic intraspinal infusion exogenous hSOD1 significantly delayed disease progression endpoint SOD1(G93A) rats. Collectively, these results suggest novel roles for support causal relationship between intraneuronal