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; R Grace Zhai

doi:10.1038/s41467-017-01289-7

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

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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, …

Nature communications, Vol.8(1), pp.1257-15

2017-11-02

DOI: https://doi.org/10.1038/s41467-017-01289-7

PMCID: PMC5668419

PMID: 29097652

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.320 Molecular & Cell Biology - Polyamines & Paraquat; 1.320.1324 Polyamines
Web Of Science research areas: Biochemistry & Molecular Biology
ESI research areas: Molecular Biology & Genetics

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Title: Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome
Creators: Chong Li - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Jennifer M Brazill - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
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, Yantai, Shandong, 264005, China
Christofer Bello - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Yi Zhu - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Marie Morimoto - Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
Lauren Cascio - JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, 29646, USA
Rini Pauly - JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, 29646, USA
Zoraida Diaz-Perez - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
May Christine V Malicdan - Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
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, Yantai, Shandong, 264005, China
Luigi Boccuto - JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, 29646, USA
Charles E Schwartz - JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, 29646, USA
William A Gahl - Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
Cornelius F Boerkoel - Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada
R Grace Zhai - 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, Yantai, Shandong, 264005, China. gzhai@med.miami.edu
Publication Details: Nature communications, Vol.8(1), pp.1257-15
Publisher: England
Academic Unit: Miller School of Medicine; Molecular and Cellular Pharmacology Research
Language: English
Resource Type: Journal article
PMID: 29097652
PMCID: PMC5668419
Record Identifier: 991031577417602976