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Sphingolipids and Myelin Structure

By

Amr S. Moustafa M.D.; Ph.D.

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OutlinesObjectives

Background

Key principles

Take home message

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ObjectivesSphingolipids:

Chemical structureTissue distribution and functions

Biochemical structure of myelin

Biosynthesis of sphingolipids

Sphingolipidosis

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Sphingolipids: BackgroundEssential component of membranes

Abundant in nervous tissue

Extra-nervous tissue:

e.g., Receptors for

Cholera toxins

Diphtheria toxins

Viruses

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Regulation of growth & development

Very antigenic:

Blood group antigen

Embryonic antigenTumor antigen

Cell transformation

Sphingolipids: BackgroundCONTD

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Chemical Structure of sphingolipids

Types:Glycosphingolipids (Glycolipids)

Sphingophospholipids e.g., Sphingomyelin

Myelin structure and function

Sphingolipidosis

Key Principles

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Sphingolipids:Structure and Types

Ceramide=Sphingosine +fatty acid

Sphingomyelin=Ceramide +Phosphorylcholine

Cerebrosides=Ceramide +Monosaccharides

Gangliosides=Ceramide oligosaccharides +NANA

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SphingosineCH3 (CH2)12 CH CH CH CH CH2OH

OH NH2

Long chain, unsaturated amino alcohol

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CeramideCH3 (CH2)12 CH CH CH CH CH2OH

OH NH

C

O

(CH2)nCH3

Long Chain Fatty acid

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SphingomyelinCH3 (CH2)12 CH CH CH CH CH2O

OH NH

C

O

(CH2)nCH3

Long Chain Fatty acid

Phosphorylcholine

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Galactocerebroside

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Gangliosides

GM2

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phingolipids ynthesis

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Myelin StructureMyelinis a specialized cell membrane that ensheathes an axon

to form a myelinated nerve fiber

Myelin is produced by:

Schwann cells: Peripheral nerves

Oligodendrocytes: CNS

Myelin composition:Lipids (80%): Main component: Cerebrosides

Other component: Sphingomyelin

Proteins (20%): e.g., Myelin basic protein

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Myelin StructureFatty acid of Sphingomyelin:

Myelin sheath:Very long chain fatty acids:

Lignoceric 24:0

Nervonic 24:1

Gray matter:Long chain fatty acid

Stearic 18:0

CONTD

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Myelin Structure and FunctionMyelin 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

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SphingolipidosisSynthesis (Normal);Degradation (Defective)

Substrate accumulates in organs

Progressive, early death

Phenotypic and genotypic variability

Autosomal recessive (mostly)

Rare, Except inAshkenazi Jewish

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SphingolipidosisMeasure enzyme activity

Cultured fibroblasts or peripheral leukocytes

Cultured amniocytes (prenatal)Histologic examination

DNA analysis

Replacement Therapy:

Recombinant human enzyme

Bone marrow transplantation:Gaucher disease

Diagnosis:

Treatment:

CONTD

CO

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Sphingolipidosis CONTD

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Niemann - Pick Disease

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Gaucher Disease

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Take Home Message 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 found also 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 degradation of sphingolipids

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