Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.

Overview

1. Childhood Dementia Research Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
2. Department of Molecular and Biomedical Science, School of Biological Sciences, the University of Adelaide, Adelaide, South Australia, Australia

Abstract

Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up‐regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down‐regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short‐term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4‐week study in pre‐symptomatic MPS IIIA mice (3‐ or 6‐mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer‐term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. The metabolomics data has been deposited in a publicly available repository. The raw metabolomics data is available from the Metabolomics Workbench ST004530. All code to reproduce the metabolomics analysis can be found at https://github.com/karissa‐b/2025_Drosophila_MPSIII_metabolomics (https://github.com/karissa-b/2025_Drosophila_MPSIII_metabolomics).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: — → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 11 MeSH terms, 4 funders, 110 references.

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This paper

Beard, H., Dayan, S., Barthelson, K., Hewson, L., O'Keefe, L. V., & Hemsley, K. M. (2026). Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III. Journal of inherited metabolic disease, 49(3), e70195. https://doi.org/10.1002/jimd.70195

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