TY - JOUR
T1 - Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome
AU - Li, Chong
AU - Brazill, Jennifer M.
AU - Liu, Sha
AU - Bello, Christofer
AU - Zhu, Yi
AU - Morimoto, Marie
AU - Cascio, Lauren
AU - Pauly, Rini
AU - Diaz-Perez, Zoraida
AU - Malicdan, May Christine V.
AU - Wang, Hongbo
AU - Boccuto, Luigi
AU - Schwartz, Charles E.
AU - Gahl, William A.
AU - Boerkoel, Cornelius F.
AU - Zhai, R. Grace
N1 - Funding Information:
We are grateful to all SRS families. We thank T. Koerner, M. Raymond, and all members of the Snyder-Robinson foundation for their support. We thank Y. Moon, J.E. Balke, Y. Meng, Y. Huang (NIH-UDP), and J. Guo (NIH-UDP) for technical assistance; A. Barrientos for reagents; G. Juhasz and E.H. Baehrecke for Reference(2) P antibody, M.R. Bates and V.W. Almeida from the Electron Microscopy Core Facility at the University of Miami for their assistance; K. Ruan and J.S. Park for technical suggestions and discussions. This work is supported by the Snyder-Robinson Foundation Predoctoral Fellowship (to C.L.), the Dr. John T. Macdonald Foundation (to C.L.), the Lois Pope LIFE Fellows Program (to C.L., Y.Z., and J.M.B.), the Sheila and David Fuente Neuropathic Pain Research Program Graduate Fellowship (to J.M.B.), contracts, grants from National Institutes of Health (NIH) HHSN268201300038C, HHSN268201400033C, and R21GM119018 (to R.G.Z.), and by Taishan Scholar Project (Shandong Province, People’s Republic of China).
Publisher Copyright:
© 2017 The Author(s).
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01289-7
DO - 10.1038/s41467-017-01289-7
M3 - Article
C2 - 29097652
AN - SCOPUS:85032973409
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1257
ER -