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Sphingolipids and Myelin Structure

Dive into the biochemical structure of sphingolipids, their functions, myelin composition, and sphingolipidoses. Explore key principles, such as myelin sheath function, synthesis, and diagnostic methods for sphingolipidoses.

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Sphingolipids and Myelin Structure

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  1. Sphingolipids and Myelin Structure

  2. Outlines • Objectives. • Background. • Key principles. • Take home messages.

  3. Objectives By the end of this lecture, the students should be able to: • Recognize the Sphingolipids class of lipids as regard their chemical structure, tissue distribution and functions. • Be familiar with the biochemical structure and function of myelin. • Learn the basics of biosynthesis of sphingolipids. • Be introduced to Sphingolipidoses.

  4. BACKGROUND • There are two classes of phospholipids based on the backbone: • Glycerol (from glucose). • Sphingosine (from serine and palmitate).

  5. BACKGROUND (Cont’d…) • Essential component of membranes. • Abundant in nervous tissue. • Also exist extra-nervous tissue: • e.g. Receptors for: • Cholera toxins • Diphtheria toxins • Viruses.

  6. BACKGROUND (Cont’d…) • Regulation of growth and development. • Very antigenic: • Blood group antigen • Embryonic antigen • Tumor antigen • Cell transformation.

  7. Key Principles • Chemical structure of Sphingolipids. • Types: • Glycosphingolipids (Glycolipids). • Sphingophospholipids, e.g. Sphingomyelin. • Myelin structure and function. • Sphingolipidoses.

  8. Sphingolipids:Structure and types

  9. Sphingosine Long chain, unsaturated amino alcohol CH3 (CH2)12 CH CH CH CH CH2OH OH NH2

  10. Ceramide Ceramide = Sphingosine + Fatty acid Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2OH OH NH C (CH2)n CH3 O • Ceramide play a key role in maintaining the skin’s water-permeability barrier. • Decreased ceramide levels are associated with a number of skin diseases.

  11. Sphingomyelin Sphingomyelin = Ceramide + Phosphorylcholine Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2O Phosphorylcholine OH NH C (CH2)n CH3 O • Sphingomyelin is the only significant sphingolipid in humans

  12. Cerebrosides Cerebrosides = Ceramide + Monosaccharides e.g. Galactocerebroside.

  13. Gangliosides Gangliosides = Ceramide oligosaccharides + NANA e.g. GM2. • For GM2: G=ganglioside; M=mono molecule of NANA; 2=the monomeric sequence of the carbohydrate attached to the ceramide (NANA)

  14. Sphingolipids’ Synthesis

  15. Myelin Structure Myelinis a specialized cell membrane that ensheathes an axon to form a myelinated nerve fiber. Myelinis produced by: Schwann cells:Peripheral nerves. Oligodendrocytes: CNS. Myelincomposition: Lipids (80%):Main component:Cerebrosides Other component: Sphingomyelin Proteins (20%): e.g. Myelin basic protein

  16. Myelin Structure Fatty acid of Sphingomyelin: Myelin sheath: Very long chain fatty acids Lignoceric 24:0 Nervonic 24:1(15)

  17. Myelin Structure and function Myelin sheath insulates the nerve axon to avoid signal leakage and greatly speeds up the transmission of impulses along axons. Multiple sclerosis: Neuro-degenerative, auto-immune disease. Breakdown of myelin sheath (demyelination). Defective transmission of nerve impulses. Direction of nerve impulse

  18. SphingolipidosEs • A partial or total missing of a specific lysosomal acid hydrolase leads to accumulation of a sphingolipid. • Lysosomal lipid storage diseases caused by these deficiencies are called sphingolipidoses.

  19. SPHINGOLIPIDOSES (Cont’d…) • Synthesis (Normal); Degradation (Defective). • Substrate accumulates in organs.. • Progressive, early death. • Phenotypic and genotypic variability. • Autosomal recessive (mostly). • Rare, Except in Ashkenazi Jewish. • Usually only a single sphingolipid accumulates in the involved organs in each disease

  20. SPHINGOLIPIDOSES (Cont’d…) • Diagnosis: • Measure enzyme activity: • Cultured fibroblasts or peripheral leukocytes. • Cultured amniocytes or chorionic villi (prenatal). • Histologic examination. • DNA analysis. • Treatment: e.g. for Gaucher disease: • Replacement Therapy (e.g. recombinant human enzyme). • Bone marrow transplantation.

  21. SphingolipidosEs

  22. Niemann-pick disease

  23. Gaucher disease

  24. Take home messages • Sphingolipids are complex lipids that includes sphingo-phospholipids and glycolipids. • Ceramide is the precursor of all sphingolipids. • Sphingolipids are present mainly in nerve tissue, but they are also found extra-neural. • Myelin sheath insulates the nerve axon to avoid signal leakage and speed up impulse transmission. • Sphingolipidoses are rare genetic diseases due to defective degeneration of sphingolipids.

  25. Reference Lippincott Illustrated Review of Biochemistry, 6th edition, 2014, Unit 3, Chapter 17, Pages 201-218.

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