ArticleCellular and molecular life sciences : CMLS2023
Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.
Article in Cellular and molecular life sciences : CMLS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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14 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Pooled it
- Exosome Proteomics of SOD1Annals of clinical and translational neurology · 2026Article
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- Landscapes of missense variant impact for human superoxide dismutase 1.American journal of human genetics · 2025Article
- Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.ACS pharmacology & translational science · 2025Review
- RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.International journal of molecular sciences · 2025Review
- Inhibition of SOD1 trimerization is a novel drug target for ALS disease.Translational neurodegeneration · 2025Article
- From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine.International journal of molecular sciences · 2025Review
- Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.International journal of molecular sciences · 2024Review
- SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.Database : the journal of biological databases and curation · 2024Article
- Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.Translational neurodegeneration · 2024Review
- Oxidized SOD1 accelerates cellular senescence in neural stem cells.Stem cell research & therapy · 2024Article
- Review
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.
methodsBased on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.
resultsExpression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.
conclusionsThe CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.
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