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MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous
Eiichi Tokuda1, Yume Sakashita1, Naoya Tokoro1
1Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Chiba, Japan.
International Journal of Molecular Sciences
|June 19, 2024
Summary
Antibodies targeting misfolded superoxide dismutase-1 (SOD1) recognize zinc-deficient and conformation-disordered SOD1 species, offering insights into amyotrophic lateral sclerosis (ALS) pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Misfolding of superoxide dismutase-1 (SOD1) is a key pathological feature in amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations.
- Understanding the specific misfolded SOD1 species recognized by antibodies is crucial for elucidating SOD1's role in ALS pathogenesis.
Purpose of the Study:
- To molecularly characterize the recognition profile of the MS785-MS27 antibody cocktail against various SOD1 conformers.
- To investigate the pathological relevance of antibody-recognized SOD1 species in ALS models.
Main Methods:
- Indirect Enzyme-Linked Immunosorbent Assay (ELISA) to assess antibody binding to different SOD1 species.
- Motor neuron cell-based cytotoxicity assays.
- Immunohistochemistry in SOD1G93A mouse models of ALS.
Main Results:
- The MS785-MS27 antibody cocktail recognized both wild-type and mutated SOD1 species that were zinc-deficient or conformationally disordered (unfolded, oligomeric).
- The antibodies showed lower affinity for aggregated SOD1 forms.
- Antibody-reactive SOD1 induced motor neuron cytotoxicity, which was mitigated by zinc treatment.
- Immunohistochemistry revealed antibody-reactive SOD1 primarily in spinal motor neurons of SOD1G93A mice, with distinct distribution patterns during disease progression.
Conclusions:
- The MS785-MS27 antibody cocktail identifies diverse, conformationally disordered SOD1 species, particularly those lacking zinc.
- These findings highlight the heterogeneity of misfolded SOD1 in ALS pathogenesis and provide specific targets for diagnostic and therapeutic strategies.
