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Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS
Helen Beard1, Sonia Dayan2, Karissa Barthelson1,2
1Childhood Dementia Research Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, 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.
Insights
Spermidine supplementation shows promise for Mucopolysaccharidosis type III (MPS III), a rare neurodegenerative disease. Studies in fly and mouse models revealed reduced disease markers and improved activity, warranting further investigation in humans.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Mucopolysaccharidosis type III (MPS III) is a fatal neurodegenerative lysosomal storage disorder with no approved treatments.
- Disease progression involves cognitive and physical decline, typically leading to death in early adulthood.
Purpose of the Study:
- To investigate spermidine supplementation as a potential therapeutic for MPS III.
- To characterize the metabolomic changes in MPS III models and explore spermidine's mechanism of action.
Main Methods:
- Metabolomic analysis of Drosophila melanogaster models of MPS IIIA and MPS IIIC.
- Oral spermidine supplementation in MPS III fly models and MPS IIIA mice.
- Assessment of behavioral changes, microgliosis, lysosomal size, and astroglial response.
Main Results:
- MPS III flies exhibited metabolic derangements, with altered nucleotide, purine, ascorbate, and aldarate metabolism.
- Spermidine levels decreased with age in MPS III fly models.
- Spermidine supplementation improved activity in fly models and reduced astroglial response in MPS IIIA mice, but did not affect microgliosis or lysosomal size.
Conclusions:
- Spermidine supplementation may offer a therapeutic avenue for MPS III by mitigating key pathological features.
- Further long-term studies in larger animal cohorts are essential to confirm spermidine's efficacy in preventing or slowing disease progression.
