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

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.

• Authors: 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, R Grace Zhai
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1257 (11 02 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29097652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Drosophila Proteins
• Polyamines
• Reactive Oxygen Species
• Electron Transport Complex IV
• Spermine Synthase
• Spermidine

Topics

• Animals
• Animals, Genetically Modified
• Antioxidants (pharmacology)
• Autophagy (genetics)
• Brain (drug effects, metabolism, ultrastructure)
• Disease Models, Animal
• Drosophila Proteins (genetics)
• Drosophila melanogaster
• Electron Transport Complex IV (metabolism)
• Electroretinography
• Humans
• Lysosomes (metabolism)
• Mental Retardation, X-Linked (genetics, metabolism)
• Microscopy, Electron, Transmission
• Oxidative Stress (genetics)
• Polyamines (metabolism)
• Reactive Oxygen Species (metabolism)
• Retinal Neurons (drug effects, ultrastructure)
• Spermidine (metabolism)
• Spermine Synthase (deficiency, genetics, metabolism)
• Survival Rate
• Synapses (drug effects, ultrastructure)