Storage of mutant human sod1 in non‐neural cells from the type‐1 amyotrophic lateral sclerosis ratg93a model correlated with the lysosomes’ dysfunction

Ilaria Bicchi, Francesco Morena, Chiara Argentati, Laura Rota Nodari, Carla Emiliani, Maurizio Gelati, Angelo L. Vescovi, Sabata Martino

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number1080
JournalBiomedicines
Volume9
Issue number9
DOIs
StatePublished - 2021

Keywords

  • ALS
  • Autophagy
  • Bone marrow‐mesenchymal stem cells
  • GALC
  • Hexosaminidase
  • LC3
  • Lysosomal storage disorders
  • Mutant SOD1 lysosomal storage

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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