Glycation modulates superoxide dismutase 1 aggregation and toxicity in models of sporadic amyotrophic lateral sclerosis.

Autor: Monteiro Neto JR; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany., Ribeiro GD; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil., Magalhães RSS; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil., Follmer C; Laboratory of Biological Chemistry of Neurodegenerative Disorders, Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil., Outeiro TF; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany; Max Planck Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany., Eleutherio ECA; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil. Electronic address: eliscael@iq.ufrj.br.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2023 Dec; Vol. 1869 (8), pp. 166835. Date of Electronic Publication: 2023 Aug 07.
DOI: 10.1016/j.bbadis.2023.166835
Abstrakt: Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.
Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose. All authors declare that there are notcompeting financial interests in relation to this work. Elis Cristina Araujo Eleutherio reports financial support was provided by Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State. Tiago Fleming Outeiro reports financial support was provided by German Research Foundation. Cristian Follmer reports financial support was provided by Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State. Elis Cristina Araujo Eleutherio reports financial support was provided by Coordination of Higher Education Personnel Improvement.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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