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      Evaluating disease-modifying effects of a sigma-1 receptor agonist in an animal model of ALS

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          Around 12-20% of familial amyotrophic lateral sclerosis (fALS) are related to mutations in Cu/Zn superoxide dismutase (SOD1) that produce degeneration of motor neurons by a toxic gain-of-function. The insertion of the human SOD1 G93A mutation in transgenic mice produces cachexia, hindlimb paralysis and subsequent death due to SOD1 protein misfolding and aggregation. The sigma-1 receptor (S1R) prevents aberrant protein conformations by acting as a molecular chaperone. In addition, some mutations in S1R are linked to juvenile ALS indicating an important role for S1R. Here, we used a delayed onset G93A mouse model that allowed for a prolonged monitoring of preclinical symptoms before onset of the severe phenotype with subsequent death at 28-32 weeks. At 18 weeks of age, and prior to the appearance of any symptoms, S1R agonist or vehicle was continuously administered during 4 weeks by subcutaneous osmotic pumps. Mice were monitored weekly and three behavioral tests were used to monitor muscle strength, motor coordination and balance: Inverted Screen Test (IST), the Pole Test (PT) and Gait Analysis. We found that mice treated with S1R agonist were resistant to weight loss observed in vehicle treated mice and this negatively affected performance in IST and PT, where significant differences between groups were not observed. However, 5 weeks after S1R agonist treatment had ended, improved parameters in Gait Analysis were observed in treated mice compared to untreated mice. Our results indicate that a S1R agonist can modify the progression of ALS-associated motor deficits in a delayed onset SOD-1 G93A mouse model.

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          ScienceOpen Posters
          10 July 2020
          [1 ] Universidad de La Laguna
          [2 ] Umeå University

          This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at .


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