TY - JOUR
T1 - (R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder-Robinson syndrome
AU - Stewart, Tracy Murray
AU - Khomutov, Maxim
AU - Foley, Jackson R.
AU - Guo, Xin
AU - Holbert, Cassandra E.
AU - Dunston, Tiffany T.
AU - Schwartz, Charles E.
AU - Gabrielson, Kathleen
AU - Khomutov, Alexey
AU - Casero, Robert A.
N1 - Funding Information:
This work was supported by NCI, National Institutes of Health Grants R01CA204345 and R01CA235863 (to R. A. C.), P30CA006973 (to S. K. C. C. C.) and R21CA229582 (to K. G.) and NINDS, National Institutes of Health Grant R01NS073854 (to C. E. S.). This work was also supported by fund-ing from the Million Dollar Bike Ride, Orphan Disease Center at the University of Pennsylvania Grants MDBR-18-127-SR (to R. A. C.) and MDBR-20-135-SRS (to R. A. C. and T. M. S.) and a grant from the South Carolina Department of Disabilities and Special Needs (to C. E. S.). Syn-thesis of 1,12-Me2SPM was supported by Russian Science Foundation Grant 17-74-20049 (to A. K.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily repre-sent the official views of the National Institutes of Health.
Funding Information:
This work was supported by NCI, National Institutes of Health Grants R01CA204345 and R01CA235863 (to R. A. C.), P30CA006973 (to S. K. C. C. C.) and R21CA229582 (to K. G.) and NINDS, National Institutes of Health Grant R01NS073854 (to C. E. S.). This work was also supported by funding from the Million Dollar Bike Ride, Orphan Disease Center at the University of Pennsylvania Grants MDBR-18-127-SR (to R. A. C.) and MDBR-20-135-SRS (to R. A. C. and T. M. S.) and a grant from the South Carolina Department of Disabilities and Special Needs (to C. E. S.). Synthesis of 1,12-Me2SPM was supported by Russian Science Foundation Grant 17-74-20049 (to A. K.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Murray Stewart et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020/3/6
Y1 - 2020/3/6
N2 - Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome caused by a loss-of-function mutation in the spermine synthase (SMS) gene. Primarily affecting males, the main manifestations of SRS include osteoporosis, hypotonic stature, seizures, cognitive impairment, and developmental delay. Because there is no cure for SRS, treatment plans focus on alleviating symptoms rather than targeting the underlying causes. Biochemically, the cells of individuals with SRS accumulate excess spermidine, whereas spermine levels are reduced. We recently demonstrated that SRS patient-derived lymphoblastoid cells are capable of transporting exogenous spermine and its analogs into the cell and, in response, decreasing excess spermidine pools to normal levels. However, dietary supplementation of spermine does not appear to benefit SRS patients or mouse models. Here, we investigated the potential use of a metabolically stable spermine mimetic, (R,R)-1,12-dimethylspermine (Me2SPM), to reduce the intracellular spermidine pools of SRS patient-derived cells. Me2SPM can functionally substitute for the native polyamines in supporting cell growth while stimulating polyamine homeostatic control mechanisms. We found that both lymphoblasts and fibroblasts from SRS patients can accumulate Me2SPM, resulting in significantly decreased spermidine levels with no adverse effects on growth. Me2SPM administration to mice revealed that Me2SPM significantly decreases spermidine levels in multiple tissues. Importantly, Me2SPM was detectable in brain tissue, the organ most affected in SRS, and was associated with changes in polyamine metabolic enzymes. These findings indicate that the (R,R)-diastereomer of 1,12-Me2SPM represents a promising lead compound in developing a treatment aimed at targeting the molecular mechanisms underlying SRS pathology.
AB - Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome caused by a loss-of-function mutation in the spermine synthase (SMS) gene. Primarily affecting males, the main manifestations of SRS include osteoporosis, hypotonic stature, seizures, cognitive impairment, and developmental delay. Because there is no cure for SRS, treatment plans focus on alleviating symptoms rather than targeting the underlying causes. Biochemically, the cells of individuals with SRS accumulate excess spermidine, whereas spermine levels are reduced. We recently demonstrated that SRS patient-derived lymphoblastoid cells are capable of transporting exogenous spermine and its analogs into the cell and, in response, decreasing excess spermidine pools to normal levels. However, dietary supplementation of spermine does not appear to benefit SRS patients or mouse models. Here, we investigated the potential use of a metabolically stable spermine mimetic, (R,R)-1,12-dimethylspermine (Me2SPM), to reduce the intracellular spermidine pools of SRS patient-derived cells. Me2SPM can functionally substitute for the native polyamines in supporting cell growth while stimulating polyamine homeostatic control mechanisms. We found that both lymphoblasts and fibroblasts from SRS patients can accumulate Me2SPM, resulting in significantly decreased spermidine levels with no adverse effects on growth. Me2SPM administration to mice revealed that Me2SPM significantly decreases spermidine levels in multiple tissues. Importantly, Me2SPM was detectable in brain tissue, the organ most affected in SRS, and was associated with changes in polyamine metabolic enzymes. These findings indicate that the (R,R)-diastereomer of 1,12-Me2SPM represents a promising lead compound in developing a treatment aimed at targeting the molecular mechanisms underlying SRS pathology.
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U2 - 10.1074/jbc.RA119.011572
DO - 10.1074/jbc.RA119.011572
M3 - Article
C2 - 31996374
AN - SCOPUS:85081045285
SN - 0021-9258
VL - 295
SP - 3247
EP - 3256
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -