Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome

Chong Li, Jennifer M. Brazill, Sha Liu, Christofer Bello, Yi Zhu, Marie Morimoto, Lauren Cascio, Rini Pauly, Zoraida Diaz-Perez, May Christine V. Malicdan, Hongbo Wang, Luigi Boccuto, Charles E. Schwartz, William A. Gahl, Cornelius F. Boerkoel and R. Grace Zhai ()
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Chong Li: University of Miami Miller School of Medicine
Jennifer M. Brazill: University of Miami Miller School of Medicine
Sha Liu: School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University
Christofer Bello: University of Miami Miller School of Medicine
Yi Zhu: University of Miami Miller School of Medicine
Marie Morimoto: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, NIH
Lauren Cascio: JC Self Research Institute, Greenwood Genetic Center
Rini Pauly: JC Self Research Institute, Greenwood Genetic Center
Zoraida Diaz-Perez: University of Miami Miller School of Medicine
May Christine V. Malicdan: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, NIH
Hongbo Wang: School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University
Luigi Boccuto: JC Self Research Institute, Greenwood Genetic Center
Charles E. Schwartz: JC Self Research Institute, Greenwood Genetic Center
William A. Gahl: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, NIH
Cornelius F. Boerkoel: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, NIH
R. Grace Zhai: University of Miami Miller School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Polyamines are tightly regulated polycations that are essential for life. Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome; however, little is known about the neuropathogenesis of the disease. Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. SMS deficiency leads to excessive spermidine catabolism, which generates toxic metabolites that cause lysosomal defects and oxidative stress. Consequently, autophagy–lysosome flux and mitochondrial function are compromised in the Drosophila nervous system and SRS patient cells. Importantly, oxidative stress caused by loss of SMS is suppressed by genetically or pharmacologically enhanced antioxidant activity. Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders.

Date: 2017
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DOI: 10.1038/s41467-017-01289-7

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