RESUMO
The originally published version of this Article contained errors in Figure 1. In panel c, the grey shading denoting evolutionary conservation and the arrowheads indicating amino acids affected in Snyder-Robinson syndrome were displaced relative to the sequence. These errors have now been corrected in both the PDF and HTML versions of the manuscript.
RESUMO
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.
Assuntos
Autofagia/genética , Encéfalo/metabolismo , Proteínas de Drosophila/genética , Lisossomos/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Estresse Oxidativo/genética , Poliaminas/metabolismo , Espermina Sintase/genética , Sinapses/ultraestrutura , Animais , Animais Geneticamente Modificados , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Drosophila melanogaster , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Eletrorretinografia , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Microscopia Eletrônica de Transmissão , Espécies Reativas de Oxigênio/metabolismo , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/ultraestrutura , Espermidina/metabolismo , Espermina Sintase/deficiência , Espermina Sintase/metabolismo , Taxa de Sobrevida , Sinapses/efeitos dos fármacosRESUMO
Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.