ArticleProceedings of the National Academy of Sciences of the United States of America2013
Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 56 citations in OpenAlex.
- Contrasting roles of autophagy in cellular prion infection.Autophagy · 2025Article
- HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.Journal of neurochemistry · 2025Article
- Misfolding at the synapse: A role in amyotrophic lateral sclerosis pathogenesis?Frontiers in molecular neuroscience · 2022Review
- Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression.Pharmaceutics · 2021Article
- Amyotrophic Lateral Sclerosis Modifiers inGenetics · 2020Article
- The multifaceted role of kinases in amyotrophic lateral sclerosis: genetic, pathological and therapeutic implications.Brain : a journal of neurology · 2020Review
- Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones.The Journal of biological chemistry · 2020Article
- Functions of p38 MAP Kinases in the Central Nervous System.Frontiers in molecular neuroscience · 2020Review
- Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease.Advances in experimental medicine and biology · 2020Review
- Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD.Frontiers in neuroscience · 2019Review
- Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding.Biological chemistry · 2018Review
- Mechanisms of protein toxicity in neurodegenerative diseases.Cellular and molecular life sciences : CMLS · 2018Review
- Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?Neurobiology of disease · 2017Review
- Substrate binding by the yeast Hsp110 nucleotide exchange factor and molecular chaperone Sse1 is not obligate for its biological activities.Molecular biology of the cell · 2017Article
- ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation.Scientific reports · 2017Article
- An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) NaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.Human gene therapy · 2016Article
- Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications.Frontiers in immunology · 2016Review
- Prion aggregate structure in yeast cells is determined by the Hsp104-Hsp110 disaggregase machinery.The Journal of cell biology · 2015Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
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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