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Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis
Elisa Onesto1, Paola Rusmini, Valeria Crippa
1Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, Milano, Italy.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal motoneuronal disease which occurs in sporadic or familial forms, clinically indistinguishable. About 15% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene that may induce misfolding in the coded protein, exerting neurotoxicity to motoneurons. However, other cell types might be target of SOD1 toxicity, because muscle-restricted expression of mutant SOD1 correlates with muscle atrophy and motoneurons death. We analysed the molecular behaviour of mutant SOD1 in motoneuronal NSC34 and muscle C2C12 cells. We found that misfolded mutant SOD1 clearance is much more efficient in muscle C2C12 than in motoneuronal NSC34 cells. Mutant SOD1 forms aggregates and impairs the proteasome only in motoneuronal NSC34 cells. Interestingly, NSC34 cells expressing mutant SOD1 are more sensitive to a superoxide-induced oxidative stress. Moreover, in muscle C2C12 cells mutant SOD1 remains soluble even when proteasome is inhibited with MG132. The higher mutant SOD1 clearance in muscle cells correlates with a more efficient proteasome activity, combined with a robust autophagy activation. Therefore, muscle cells seem to better manage misfolded SOD1 species, not because of an intrinsic property of the mutant protein, but in function of the cell environment, indicating also that the SOD1 toxicity at muscle level may not directly depend on its aggregation rate.
Insights
Muscle cells clear misfolded mutant superoxide dismutase 1 (SOD1) more efficiently than motoneurons. This difference in clearance, not protein aggregation, may explain SOD1 toxicity in amyotrophic lateral sclerosis (ALS).
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.
- Mutations in the superoxide dismutase 1 (SOD1) gene cause familial ALS, leading to protein misfolding and neurotoxicity.
- The role of non-neuronal cells, like muscle cells, in SOD1 toxicity is not fully understood.
Purpose of the Study:
- To investigate the molecular behavior and clearance mechanisms of mutant SOD1 in motoneuronal and muscle cells.
- To compare the cellular response to misfolded SOD1 in different cell types.
- To elucidate the factors contributing to SOD1-associated toxicity in ALS.
Main Methods:
- Utilized motoneuronal NSC34 and muscle C2C12 cell lines.
- Analyzed mutant SOD1 aggregation, clearance, and proteasome function.
- Assessed cellular sensitivity to oxidative stress.
- Investigated the impact of proteasome inhibition (MG132) on mutant SOD1 solubility.
Main Results:
- Misfolded mutant SOD1 clearance is significantly more efficient in muscle C2C12 cells than in motoneuronal NSC34 cells.
- Mutant SOD1 aggregates and impairs proteasome function specifically in motoneuronal cells.
- Muscle cells exhibit higher proteasome activity and autophagy activation, contributing to better mutant SOD1 management.
- Muscle cells expressing mutant SOD1 are less sensitive to oxidative stress and maintain SOD1 solubility even with proteasome inhibition.
Conclusions:
- Muscle cells possess superior mechanisms for clearing misfolded SOD1 compared to motoneurons.
- Cellular environment, including proteasome and autophagy efficiency, dictates mutant SOD1 management.
- SOD1 toxicity at the muscle level may not be solely dependent on protein aggregation rates.
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