Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome
Abstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317833 |
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| author | Tracy Murray Stewart Jackson R Foley Cassandra E Holbert Maxim Khomutov Noushin Rastkari Xianzun Tao Alex R Khomutov R Grace Zhai Robert A Casero |
| author_facet | Tracy Murray Stewart Jackson R Foley Cassandra E Holbert Maxim Khomutov Noushin Rastkari Xianzun Tao Alex R Khomutov R Grace Zhai Robert A Casero |
| author_sort | Tracy Murray Stewart |
| collection | DOAJ |
| description | Abstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2‐difluoromethylornithine (DFMO), an FDA‐approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential. |
| format | Article |
| id | doaj-art-5cc8bb3c21394af3a39b11fa46178f84 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-5cc8bb3c21394af3a39b11fa46178f842025-08-20T04:02:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-09-01151111110.15252/emmm.202317833Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndromeTracy Murray Stewart0Jackson R Foley1Cassandra E Holbert2Maxim Khomutov3Noushin Rastkari4Xianzun Tao5Alex R Khomutov6R Grace Zhai7Robert A Casero8Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineEngelhardt Institute of Molecular Biology, Russian Academy of SciencesSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of MedicineEngelhardt Institute of Molecular Biology, Russian Academy of SciencesDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineAbstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2‐difluoromethylornithine (DFMO), an FDA‐approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.https://doi.org/10.15252/emmm.202317833alpha‐methylated polyamine analogueeflornithineS‐adenosylmethionine decarboxylasespermidinespermine synthase |
| spellingShingle | Tracy Murray Stewart Jackson R Foley Cassandra E Holbert Maxim Khomutov Noushin Rastkari Xianzun Tao Alex R Khomutov R Grace Zhai Robert A Casero Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome EMBO Molecular Medicine alpha‐methylated polyamine analogue eflornithine S‐adenosylmethionine decarboxylase spermidine spermine synthase |
| title | Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome |
| title_full | Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome |
| title_fullStr | Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome |
| title_full_unstemmed | Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome |
| title_short | Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome |
| title_sort | difluoromethylornithine rebalances aberrant polyamine ratios in snyder robinson syndrome |
| topic | alpha‐methylated polyamine analogue eflornithine S‐adenosylmethionine decarboxylase spermidine spermine synthase |
| url | https://doi.org/10.15252/emmm.202317833 |
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