Block A: Membrane Biology & Biochemistry. Lipid signalling and sphingolipid function

Transcription

1 Block A: Membrane Biology & Biochemistry Lipid signalling and sphingolipid function Gerhild van Echten-Deckert Tel g.echten.deckert@uni-bonn.de

2 Programme of the week Monday - general discussion: cellular signalling - sphingosine-1-phosphate phosphate and neurodegeneration (Morbus Alzheimer) Tuesday - brain specific deletion of SPL and its impact on behavivour - bioactive fatty acid derivatives: endocannabinoids and eicosanoids Thursday Stefanie Herresthal: Sphingolipids: Critical Players in Alzheimer s Disease Friday Gökcen Gözüm: Targeting g sphingosine-1-phosphate p p axis in cancer

3 utline of objectives General aspects on cell signalling Signalling via: G-protein coupled receptors Receptor tyrosine kinases Nuclear receptors Signalling lipids: Fatty acids Eicosanoids Endocannabinoids Sphingolipids (S1P) Pathological implications: Neurodegeneration (Alzheimer) Inflammation Cancer References: Hagen et al. Subcellular origin of sphingosine-1-phosphate is essential for its toxic effect in lyase-deficient neurons. J. Biol. Chem. 284: (2009). Hagen et al. Sphingosine-1-phosphate links sphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism. Cell Death Differ. 18: (2011) p Walter, Jochen, van Echten-Deckert, Gerhild: Cross-talk of membrane lipids and Alzheimer-related proteins. Mol. Neurodegen. 8:34-45 (2013). van Echten-Deckert, G., Hagen-Euteneuer, N., Karaca, I., Walter, J. Sphingosine-1-phosphate: boon and bane fort he brain. Cell Physiol Biochem., 34: (2014). van Echten-Deckert t & Walter Sphingolipids: id Critical players in Alzheimer s disease Prog Lipid Res 51, (2012) Kunkel et al. Targeting g the sphingosine-1-phosphate p p axis in cancer, inflammation and beyond Nature Rev, Drug Discovery, 12: (2013). Kendall & Nicolaou Bioactive lipid mediators in skin Inflammation and immunity Prog. Lipid Res., 52: (2013).

4 Programme Introduction - Morbus Alzheimer: numbers and facts Sphingolipids: history, structure, metabolism Sphingosine-1-phosphate (S1P) boon or bane? - biological activity and mechanism of action CIMES, a synthetic sphingosine analogue S1P-lyase K and conditional K - molecular bases of S1P-induced neurotoxicity - S1P-lyase-deficiency and neurodegeneration - S1P-lyase-deficiency and synaptic plasticity Conclusion and outlook

5 1906: 37. Meeting of doctors for the insane of southwest Germany in Tübingen Alois Alzheimer reports about a peculiar affection of the cerebral cortex Auguste D. 2013: World Alzheimer Report 2013 AD most common neurodegenerative disease worldwide 36 mill. cases (2030: 77 mill. 2050: 135 mill.) Costs worldwide: 604 Bill. USD in 2010 (1% of the global GDP) 1,117 Bill USD in 2030

6 Histopathological findings reported by A. Alzheimer (1906) Miliary foci distributed all over the cortex, caused by the infiltration of a peculiar substance into the cortex Weird neurofibrillary changes, that appeared like very thick tangles filling not only the cell body but also neuronal processes Images C & D are from Holtzman et al. Sci Transl. Med. 2011, 3, 1-17

7 Key neuropathological elements of AD BAP-tists: senile (neuritic) plaques:extracellular aggregates of -amyloid TAU-ists: Neurofibrillary tangles: intracellular bundles of hyperphosphorylated tau ohcm.oxfordmedicine.com/.../graphic10017.jpeg

8 Scheme of major proteolytic processing pathways of APP A B APP S- APP S- A p3 Therapeutic approaches aimed to reduce A production/aggregation have failed! APP APP CTF APP APP CTF van Echten-Deckert & Walter, Prog Lipid Res 2012

9 Figure 3 Artistic change in an individual with Alzheimer's disease 60 years 62 years 63 years 64 years 66 years 65 years The Lancet 2001; 357:

10 Sphingolipids: History H H NH 2 Johann Ludwig Wilhelm Thudichum 1884

11 Sphingolipids - Structure H NH 2 H Sphingosine H H H H H H AcHN HC H H H AcHN H H H H H H HN H Ceramide Ganglioside GM1 H HN HN CH H 3 H 3 C N P H 3 C H Ceramide Ceramide Sphingomyelin

12 Glycosphingolipids form cell type specific profiles ligodendrocyte Neuron GalCer GlcCer Myelin Sheath Sulfatide LacCer Axon Astrocyte Endothelial Cells Gbose 3 Cer Gbose 4 Cer Neuron Muscle Fiber van Echten-Deckert & Herget, BBA 2006 Microglia G M3 G M2 G M1 G D3 G D1a G D1b G T1b

13 NH 2 NH 2 H serine H + (CH 2 ) 14/16 CSCoA palmitoyl/stearoyl-coa SPT (+PLP) Sphingolipids: Main metabolic pathways H CH3 3-ketosphinganine 3KSR (+NADPH) De novo formation NH 2 Sulfatide H H sphinganine CerS1 (+stearoyl-coa) Degradation Recycling HN GalCer H H dihydroceramide DES H HN SMS H 3C N P HN H ceramide SMase H sphingomyelin CerS1 Cerase(acid) GlcCer H NH 2 H sphingosine LacCer NH 2 SPP SK2 P H sphingosine-1-phosphate Gangliosides SPL (+PLP) phosphoethanolamine + hexa/octadecenal van Echten-Deckert & Walter, Prog Lipid Res 2012

14 Biosynthesis of major brain gangliosides Glc-T Gal-T I SAT I SAT II β 1,1 β 1,4 α 2,3 α 2,8 Cer GlcCer LacCer GM3 GD3 GalNAc-T β 1,4 GlcCer GalCer Sulfatide LacCer GM2 Gal-T II β 1,3 GD2 GM1a SAT IV α 2,3 GD1b GM3 GM2 GM1 GD1a SAT V α 2,8 GT1b GD3 GD1a GD1b GT1b GT1a GQ1b ligo Astro Neuro a-series b-series Glucose (Glc) Galactose (Gal) N-Acetylgalactosamine (GalNAc) Sialic Acid van Echten-Deckert & Walter, Prog Lipid Res 2012

15 Degradation pathways of selected glycosphingolipids affected in lysosomal storage disorders GM1- Gangliosidosis GM1 GM1- -galactosidase GM2-activator, SAP-B GM2 Tay-Sachs Sandhoff -hexosaminidasea,b GM2-activator Sialidosis GM3 sialidase SAP-B Glucose (Glc) Galactose (Gal) LacCer N-Acetylgalactosamine (GalNAc) Sialic Acid Phosphocholine van Echten-Deckert & Walter, Prog Lipid Res 2012 GlcCer Gaucher GlcCerase SAP-C acid SMase Cer Niemann-Pick A,B Farber acid Cerase SAP-C, SAP-D Sph SM

16 Physiological/clinical relevance of bioactive sphingolipids Ser + FA-CoA apoptosis p Sphingomyelin DHCer differentiation inflammation insulin resistance Ceramide C1P inflammation senescence stress response MDR glucose tolerance brain function morphogenesis tumour genesis GlcCer GSL Sa So S1P anti-apoptosis proliferation migration inflammation i angiogenesis wound healing

17 Dual Action of S1P: Extracellular Ligand and Intracellular Second Messenger growth factor S1P S1P 1-5 trimeric G-proteins sphingosine Sphingosine kinase S1P adenylate- monomeric cyclase PLC G-proteins intracellular targets? proliferation Ca 2+ homeostasis anti-apoptosis survival differentiation motility cytoskeleton rearrangements inflammation angiogenesis

18 The subcellular origin of S1P is essential for its neurotoxic effect S1P cimes Sph PM S1P Sph SK1 (LPP?) SK2 cimesp apoptotic ti SPP ER SK2 S1P S1P apoptotic Hagen et al, JBC 2009

19 Summary cimes extracellular intracellular Z-LEHD-FMK cimes SK2 Caspase-12 Caspase-9 Caspase-3 cimesp MDL ER ER-stress Ca 2+ Calpain S1P MDL SPP SK2 Sph p35 p25 CDK5 Rb P neuronal apoptosis cell cycle reactivation tau P S1P Hagen et al, Cell Death Differ, 2011

20 Conclusions Sphingosine-1-phosphate (S1P) is a neuronal death signal, when generated by SK2 and impaired degradation Calpain is an essential mediator of S1P-induced neurotoxicity n cellular and molecular level S1P neurotoxicity parallels that of A S1P-lyase expression is correlated with neuronal death S1P-lyase deficiency is correlated with Alzheimer characteristics: Hyperphosphorylation h of tau Impaired APP-processing Elevated levels of cholesteryl-ester S1P stimulates BACE1, the rate-limiting enzyme for A production (Takasugi et al., 2011, J. Neurosci.) Conditional knockout mouse: neuron specific Conditional knockout mouse: neuron-specific inactivation ofs1p-lyase