Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

Bosco, Daryl A.; Morfini, Gerardo; Karabacak, Murat; Song, Yuyu; Gros‐Louis, François; Pasinelli, Piera; Goolsby, Holly; Fontaine, Benjamin A.; Lemay, Nathan; McKenna‐Yasek, Diane; Frosch, Matthew P.; Agar, Jeffrey N.; Julien, J.P.; Brady, Scott T.; Brown, Robert H.

doi:10.1038/nn.2660

Cited by 610 publications

(704 citation statements)

References 50 publications

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“…These results parallel those reported by Bosco et al (33), in which either a different human mutant SOD1 (H46R) or hydrogen peroxide-treated WT human SOD1 had similar inhibitory effects specifically on anterograde transport in the axoplasm assay, whereas WT human SOD1 had little or no effect. The present data suggest that a variety of oligomeric forms of mutant SOD1 species may be toxic to transport, potentially including monomeric forms, but the dynamic nature of the noncrosslinked material precludes conclusions about which species might be most toxic in that context.…”

Section: G85r Sod1-yfp But Not Wt Sod1-yfp Inhibits Anterograde Fastsupporting

confidence: 90%

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

Song

Nagy

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mutant human Cu/Zn superoxide dismutase 1 (SOD1) is associated with motor neuron toxicity and death in an inherited form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease). One aspect of toxicity in motor neurons involves diminished fast axonal transport, observed both in transgenic mice and, more recently, in axoplasm isolated from squid giant axons. The latter effect appears to be directly mediated by misfolded SOD1, whose addition activates phosphorylation of p38 MAPK and phosphorylation of kinesin. Here, we observe that several different oligomeric states of a fusion protein, comprising ALS-associated human G85R SOD1 joined with yellow fluorescent protein (G85R SOD1YFP), which produces ALS in transgenic mice, inhibited anterograde transport when added to squid axoplasm. Inhibition was blocked both by an apoptosis signal-regulating kinase 1 (ASK1; MAPKKK) inhibitor and by a p38 inhibitor, indicating the transport defect is mediated through the MAPK cascade. In further incubations, we observed that addition of the mammalian molecular chaperone Hsc70, abundantly associated with G85R SOD1YFP in spinal cord of transgenic mice, exerted partial correction of the transport defect, associated with diminished phosphorylation of p38. Most striking, the addition of the molecular chaperone Hsp110, in a concentration substoichiometric to the mutant SOD1 protein, completely rescued both the transport defect and the phosphorylation of p38. Hsp110 has been demonstrated to act as a nucleotide exchange factor for Hsc70 and, more recently, to be able to cooperate with it to mediate protein disaggregation. We speculate that it can cooperate with endogenous squid Hsp(c)70 to mediate binding and/or disaggregation of mutant SOD1 protein, abrogating toxicity.

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Section: G85r Sod1-yfp But Not Wt Sod1-yfp Inhibits Anterograde Fastsupporting

confidence: 90%

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

Song

Nagy

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The phenotype of this mice recapitulates several clinical and histopathological features of both familial and sporadic forms of the human disease [3]. Moreover, it has been recently reported that alterations of the SOD1 protein are also related to sporadic ALS cases [4], increasing the interest in the study of transgenic animals.…”

Section: Introductionmentioning

confidence: 64%

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

et al. 2012

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Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1 G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1 G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca 2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

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“…This model recapitulates most relevant clinical and histopathological features of both familial and sporadic forms of the human disease [3]. It is also of relevance that alterations of the SOD1 protein have been reported in sporadic ALS patients [4], increasing the interest of this murine model. Several mechanisms have been implicated as contributors to MN death in ALS, such as glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial defects, impaired axonal transport, and inflammation [5,6].…”

Section: Introductionmentioning

confidence: 71%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

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Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

Cited by 610 publications

References 50 publications

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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