A saposin deficiency model in Drosophila: Lysosomal storage, progressive neurodegeneration and sensory physiological decline

NEUROBIOLOGY OF DISEASE

卷:98

Article

Hindle, Samantha J.^1,3  Hebbar, Sarita^2,4  Schwudke, Dominik^2,5  Elliott, Christopher J. H.¹  Sweeney, Sean T.¹ 

[1] Univ York, Dept Biol, Wentworth Way, York Y010 5DD, N Yorkshire, England

[2] Natl Ctr Biol Sci, Tata Inst Fundamental Res, Bangalore 560065, Karnataka, India

[3] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Genentech Hall,600 16th St, San Francisco, CA USA

[4] Max Planck Inst Cell Biol & Genet, D-01307 Dresden, Germany

[5] Res Ctr Borstel, Leibniz Ctr Med & Biosci, D-23845 Borstel, Germany

关键词: Prosaposin deficiency;    Saposin;    Lysosomal storage disease;    Drosophila;    Neurodegeneration;    Sphingolipids;   

DOI  :  10.1016/j.nbd.2016.11.012

来源: Elsevier

【 摘 要 】

Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence or impaired function of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. Drosophila saposin-related (dSap-r) mutants show a reduced longevity, progressive neurodegeneration, lysosomal storage, dramatic swelling of neuronal soma, perturbations in sphingolipid catabolism, and sensory physiological deterioration. Our data suggests a genetic interaction with a calcium exchanger (Cabs) pointing to a possible calcium homeostasis deficit in dSap-r mutants. Together these findings support the use of dSap-r mutants in advancing our understanding of the cellular pathology implicated in saposin deficiency and related LSDs. (C) 2016 The Authors. Published by Elsevier Inc.

【 授权许可】

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