SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production |
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Authors: | Daniel N. Mitroi Indulekha Karunakaran Markus Gräler Julie D. Saba Dan Ehninger María Dolores Ledesma |
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Affiliation: | 1. LIMES Institute, Membrane Biology and Lipid Biochemistry, University of Bonn, Bonn, Germany;2. Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany;3. Children's Hospital Oakland Research Institute, University of California, San Francisco, CA, USA;4. German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany;5. Centro Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain |
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Abstract: | Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons. SGPL1 cleaves S1P into ethanolamine phosphate, which is directed toward the synthesis of phosphatidylethanolamine (PE) that anchors LC3-I to phagophore membranes in the form of LC3-II. In the brains of SGPL1fl/fl/Nes mice with developmental neural specific SGPL1 ablation, we observed significantly reduced PE levels. Accordingly, alterations in basal and stimulated autophagy involving decreased conversion of LC3-I to LC3-II and increased BECN1/Beclin-1 and SQSTM1/p62 levels were apparent. Alterations were also noticed in downstream events of the autophagic-lysosomal pathway such as increased levels of lysosomal markers and aggregate-prone proteins such as APP (amyloid β [A4] precursor protein) and SNCA/α-synuclein. In vivo profound deficits in cognitive skills were observed. Genetic and pharmacological inhibition of SGPL1 in cultured neurons promoted these alterations, whereas addition of PE was sufficient to restore LC3-I to LC3-II conversion, and control levels of SQSTM1, APP and SNCA. Electron and immunofluorescence microscopy showed accumulation of unclosed phagophore-like structures, reduction of autolysosomes and altered distribution of LC3 in SGPL1fl/fl/Nes brains. Experiments using EGFP-mRFP-LC3 provided further support for blockage of the autophagic flux at initiation stages upon SGPL1 deficiency due to PE paucity. These results emphasize a formerly overlooked direct role of SGPL1 in neuronal autophagy and assume significance in the context that autophagy modulators hold an enormous therapeutic potential in the treatment of neurodegenerative diseases. |
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Keywords: | α-synuclein/SNCA amyloid precursor protein autophagy lysosomes neuropathology phosphatidylethanolamine sphingosine-1-phosphate lyase |
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