Optimizing the Translational Value of Mouse Models of ALS for Dysphagia Therapeutic Discovery

Abstract

The goal of this study was to compare dysphagia phenotypes in low and high copy number (LCN and HCN) transgenic superoxide dismutase 1 (SOD1) mouse models of ALS to accelerate the discovery of novel and effective treatments for dysphagia and early amyotrophic lateral sclerosis (ALS) diagnosis. Clinicopathological features of dysphagia were characterized in individual transgenic mice and age-matched controls utilizing videofluoroscopy in conjunction with postmortem assays of the tongue and hypoglossal nucleus. Quantitative PCR accurately differentiated HCN-SOD1 and LCN-SOD1 mice and nontransgenic controls. All HCN-SOD1 mice developed stereotypical paralysis in both hindlimbs. In contrast, LCN-SOD1 mice displayed wide variability in fore- and hindlimb involvement. Lick rate, swallow rate, inter-swallow interval, and pharyngeal transit time were significantly altered in both HCN-SOD1 and LCN-SOD1 mice compared to controls. Tongue weight, tongue dorsum surface area, total tongue length, and caudal tongue length were significantly reduced only in the LCN-SOD1 mice compared to age-matched controls. LCN-SOD1 mice with lower body weights had smaller/lighter weight tongues, and those with forelimb paralysis and slower lick rates died at a younger age. LCN-SOD1 mice had a 32% loss of hypoglossal neurons, which differed significantly when compared to age-matched control mice. These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.

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Acknowledgements

We graciously thank the numerous students affiliated with the Lever Lab who assisted with VFSS analysis (Kaitlin Flynn, Dana Aleman, Mitchell Allen, Victoria Caywood, Loren Littrell, Rebecca Harris Healy, Mollie Ulsas, and Elizabeth White) and histology (Iyas Daghlas, Abby Lind, Chandler DeJonge, Victoria Rufo, and Michaela Thomson).

Funding

This study was funded in part by two grants from the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (Award Numbers R03 DC0110895 and R21 DC016071; T.E. Lever), University of Missouri Research Board Grant (T.E. Lever and N.L. Nichols), and Mizzou Advantage Seed Funding (T.E. Lever and J.R. Coates). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

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Correspondence to Teresa E. Lever.

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No human participants were included in this study; only animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Osman, K.L., Kohlberg, S., Mok, A. et al. Optimizing the Translational Value of Mouse Models of ALS for Dysphagia Therapeutic Discovery. Dysphagia 35, 343–359 (2020). https://doi.org/10.1007/s00455-019-10034-9

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Keywords

  • Deglutition
  • Deglutition disorders
  • Dysphagia
  • Amyotrophic lateral sclerosis (ALS)
  • Superoxide dismutase 1 (SOD1) transgenic mouse
  • Videofluoroscopy