Abstract
Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in Caenorhabditis elegans. Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of upper and lower motor neurons in the brain and spinal cord
We found that when GFP-tagged wt-SOD1 (GFP-SOD1wt) and two mutants (GFP-SOD1G85R and GFPSOD1G93A) were expressed in HeLa cells, both mutants showed predominantly cytoplasmic distribution while GFP-SOD1wt was evenly distributed in the cytoplasm and the nucleus as expected (Figure 1A)
Proteasome inhibition for 60 min did not significantly affect the nuclear levels of GFP-SOD1G85R but again leptomycin B (LMB) treatment did (Figure 1D). These results suggest that the lack of nuclear distribution of SOD1 mutants is mediated by CRM1-dependent nuclear export
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of upper and lower motor neurons in the brain and spinal cord. Most patients die from respiratory failure in 3–5 years after disease onset (Ajroud-Driss and Siddique, 2015). About 10% of ALS cases have positive family history and are classified as familial ALS (fALS). The remaining 90% of ALS cases are classified as sporadic ALS (sALS). Mutations in over 40 genes have been associated with fALS (Ajroud-Driss and Siddique, 2015), including the first identified gene encoding Cu/Zn superoxide dismutase (SOD1) (Deng et al, 1993; Rosen et al, 1993).
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