Biochemistry NEUROPSYCHIATRY BLOCK NERV222 Lecture 1 Biochemistry of Myelin Biochemistry Department 2018/2019 Nervous system Block NERV 222 September 2018

Outlines Objectives. Background. Key principles. Take home messages. September 2018

Objectives By the end of this lecture, the students should be able to: Recognize the sphingolipids class of lipid, their chemical structure, tissue distribution and functions. Be familiar with the biochemical structure, and function of myelin. Describe the basics of biosynthesis and degradation of sphingolipids. - Discuss sphingolipidosis group of diseases. September 2018

Sphingolipids: Background Essential component of membranes. Abundant in nervous tissue. Also exist extra-nervous tissue: e.g. Cell surface receptors for cholera, diphtheria and tetanus toxins as well as for certain viruses. September 2018

Sphingolipids: Background Regulation of growth and development. Very antigenic: the carbohydrate portion of a glycolipid is the antigenic determinant Blood group antigen Embryonic antigen Tumor antigen Cell transformation. September 2018

Key Principles Chemical structure of Sphingolipids. Types: Glycosphingolipids (Glycolipids). Sphingophospholipids, e.g. Sphingomyelin. Myelin structure and function. Sphingolipidosis. September 2018

Sphingolipids: Structure and types 7/10/2019

Sphingosine CH3 (CH2)12 CH CH CH CH CH2OH OH NH2 Long chain, unsaturated amino alcohol OH NH2 September 2018

Ceramide = Sphingosine + Fatty acid Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2OH OH NH C O (CH2)n CH3 September 2018

Sphingomyelin = Ceramide + Phosphorylcholine Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2O OH NH C O (CH2)n CH3 Phosphorylcholine September 2018

Cerebrosides = Ceramide + Monosaccharides e.g. Galactocerebroside. September 2018

Gangliosides Gangliosides = Ceramide oligosaccharides + NANA e.g. GM2. September 20128

Sphingolipids’ Synthesis September 2018

Myelin Structure Myelin is a specialized cell membrane that ensheathes an axon to form a myelinated nerve fiber. Myelin is produced by: Schwann cells: Periphral nerves. Oligodendrocytes: CNS. Myelin composition: Lipids (80%): Main component: Cerebrosides Other component: Sphingomyelin Proteins (20%): e.g. Myelin basic protein September 2018

Very long chain fatty acids Myelin Structure Fatty acid of Sphingomyelin: Myelin sheath: Very long chain fatty acids Lignoceric 24:0 Nervonic 24:1 September 2018

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 September 2018

Degradation Sphingolipids are degraded by lysosomal hydrolytic enzymes. If a specific lysosomal hydrolase is partially or totally missing, a sphingolipid accumulates in the lysosomes, producing lipid storage diseases or sphingolipidosis. September 2018

Sphingolipidosis Synthesis (Normal); Degradation (Defective). Substrate accumulates in organs.. Progressive, early death. Phenotypic and genotypic variability. Autosomal recessive (mostly). Rare, Except in Ashkenazi Jewish. September 2018

Sphingolipidosis Diagnosis: Measure enzyme activity: Cultured fibroblasts or peripheral leukocytes. Cultured amniocytes (prenatal). Histologic examination. DNA analysis. Treatment: Replacement Therapy: e.g. Recombinant human enzyme. Bone marrow transplantation: e.g. Gaucher disease. September 2018

Sphingolipidosis September 2018

Niemann-pick disease September 2018

Gaucher disease September 2018

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. Sphingolipidosis are rare genetic diseases due to defective degeneration of sphingolipids. September 2018

Reference Lippincott Illustrated Review of Biochemistry, 6th edition, 2014, Unit 3, Chapter 17, Pages 201-218. . KSUMC Lecture note. September 2018

THANKS September 2018