Storage of Mutant Human SOD1 in Non-Neural Cells from the Type-1 Amyotrophic Lateral Sclerosis ratG93A Model Correlated with the Lysosomes’ Dysfunction

• Published in: Biomedicines Vol. 9; no. 9; p. 1080
• Main Authors: Bicchi, Ilaria, Morena, Francesco, Argentati, Chiara, Nodari, Laura Rota, Emiliani, Carla, Gelati, Maurizio, Vescovi, Angelo L., Martino, Sabata
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 24-08-2021; MDPI
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Animal models; autophagy; Bone marrow; Enzymes; Fibroblasts; GALC; Genes; Hexosaminidase; Homeostasis; Laboratories; LC3; lysosomal storage disorders; Lysosomes; Mesenchymal stem cells; Mesenchyme; mutant SOD1 lysosomal storage; Mutants; Mutation; Nervous system; Parkinson's disease; Pathophysiology; Proteins; Stem cell transplantation; Stem cells; Superoxide dismutase; Transgenic animals; United States > US; Italy
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines9091080

Herein, we explored the impact of the lysosome dysfunction during the progression of Amyotrophic Lateral Sclerosis type-1 (ALS1). We conducted the study in non-neural cells, primary fibroblasts (rFFFs), and bone marrow-mesenchymal stem cells (rBM-MSCs), isolated from the animal model ratG93A for ALS1 at two stages of the disease: Pre-symptomatic-stage (ALS1-PreS) and Terminal-stage (ALS1-EndS). We documented the storage of human mutant Superoxide Dismutase 1, SOD1G93A (SOD1*) in the lysosomes of ALS1-rFFFs and ALS1-rBM-MSCs and demonstrated the hallmarks of the disease in non-neural cells as in ratG93A-ALS1-tissues. We showed that the SOD1* storage is associated with the altered glycohydrolases and proteases levels in tissues and both cell types from ALS1-PreS to ALS1-EndS. Only in ALS1-rFFFs, the lysosomes lost homeostasis, enlarge drastically, and contribute to the cell metabolic damage. Contrariwise, in ALS1-rBM-MSCs, we found a negligible metabolic dysfunction, which makes these cells’ status similar to WT. We addressed this phenomenon to a safety mechanism perhaps associated with an enhanced lysosomal autophagic activity in ALS1-rBM-MSCs compared to ALS1-rFFFs, in which the lysosomal level of LC3-II/LC3I was comparable to that of WT-rFFFs. We suggested that the autophagic machinery could balance the storage of SOD1* aggregates and the lysosomal enzyme dysfunction even in ALS1-EndS-stem cells.