Molecular Alterations in Sporadic and SOD1 -ALS Immortalized Lymphocytes: Towards a Personalized Therapy

• Published in: International journal of molecular sciences Vol. 22; no. 6; p. 3007
• Main Authors: Lastres-Becker, Isabel, Porras, Gracia, Arribas-Blázquez, Marina, Maestro, Inés, Borrego-Hernández, Daniel, Boya, Patricia, Cerdán, Sebastián, García-Redondo, Alberto, Martínez, Ana, Martin-Requero, Ángeles
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.03.2021; MDPI
• Subjects: Acidification; Acids - metabolism; Aged; Aged, 80 and over; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - immunology; Antioxidants; Autophagy - genetics; bioenergetic metabolism; Bioenergetics; Cell Line, Transformed; Customization; Cytokines; Energy Metabolism; Female; Glycolysis; Heterozygote; Humans; Inflammation; Lipid peroxidation; Lipids; lymphoblast; Lymphoblastoid cell lines; Lymphoblasts; Lymphocytes; Lymphocytes - immunology; Magnetic Resonance Spectroscopy; Male; Metabolism; Metabolites; Metabolomics; Middle Aged; Mitochondria; Molecular modelling; Motor neurons; Mutation; Mutation - genetics; NF-E2-Related Factor 2 - metabolism; NRF2; Oxidative phosphorylation; Oxidative Stress; Oxygen Consumption; Patients; Phosphorylation; Precision Medicine; Reactive Oxygen Species - metabolism; Respiration; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Spectrum analysis; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Therapeutic applications; Thiobarbituric Acid Reactive Substances - metabolism; bioenergetic metabolism; autophagy; lymphoblast; NRF2; inflammation; amyotrophic lateral sclerosis; oxidative stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22063007

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the -mutated ( -ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and -ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and -ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and -ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and -ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and -ALS patients and thus, personalized medicine should be developed for each case.