56 - Sphingolipids and Sphingolipidoses

Sphingolipids

Lipids with a sphingoid base

Ceramide

Sphingosine with a fatty acid group attached

Glycosphingolipds

Sphingosine with a fatty acid group and carbohydrate group

Functions of Sphingolipids

• components of membranes and lipoproteins

• serve as second messengers or precursors to them

Functions of Glycosphingolipids

• Regulation of cell interactions

• Growth and development

• Tumoriogenic properties

• Antigenic properties

C1P

• Bioactive sphingolipid with functions of:

  • survival

  • proliferation

  • inflammation

Ceramide functions

• Bioactive sphingolipid with functions of:

  • Cell Death

  • Aopotosis

  • Senescence

  • Autophagy

  • Differentiation

Sphingosine function

Apoptosis

S1P

• Bioactive sphingolipid with functions of:

  • survival

  • proliferation

  • growth

  • angiogenesis

  • inflammation

Targeting SL metabolism in cancer

• inducing intracellular ceramide

• inhibiting S1P production and signaling

FTY 720 (Fingolimod)

Pharmacological Antagonist of S1P that can treat multiple sclerosis

Tay-Sachs disease enzyme deficiency and lipid accumulation

Hexoaminidase A; G_M2 Ganglioside

Tay-Sachs Clincal Symptoms

• ID

• Blindness

• Seizures

• Startle Response

• Cherry Red Macula

• Muscular Weakness (neurodegenration)

• Ash Jews

Fabrys’ Disease enzyme deficiency

a-Galactosidase

Fabrys’ Disease Clinical Symptoms

• Red/Purple Skin Rash

• Accumulation of Globosides

• Kidney Failure

• XLR disease

Metachromatic leukodystrophy enzyme deficiency and lipid accumulation

Arylsulfatase A; 3-sulfogalactosylceramide

Metachromatic Leukodystrophy symptoms

• ID - cognitive deterioration

• Physiologic disturbances in adults

• nerves stain yellow brown

• Demyelination

Krabbe’s Disease enzyme deficiency and lipid accumulation

beta-galactosidase; Galactosylceramide

Krabbe’s Disease Clinical Symptoms

• ID

• Mental and motor deterioration

• blindness and deafness

• myelin almost absent

• Globoid bodies in white matter of brain

Gaucher’s Disease enzyme deficiency and lipid accumulation

Beta-Glucosidase; Glucosylceramide

Gaucher’s Disease symptoms

• Hepatosplenomegaly

• erosion of long bones

• ID in infants

• most common LSD

• Type I : non-neuropathic, low but detectable enzyme activity

• Type II : acute neuropathic, NO enzyme activity, death

• Type III : intermediate

Niemann-Pick Disease enzyme deficiency and lipid accumulation

Acid Sphingomyelinase aka ASMase; Sphingomyelin

Niemann-Pick Disease symptoms

• Hepatosplenomegaly

• Cherry Red spot

• ID

• Fatal in early life

• Ashkenazi Jews

Farber’s Disease enzyme deficiency and lipid accumulation

Ceramidase; Ceramide

Farber’s Disease symptoms

• Hoarseness

• Dermatitis - SubCutaneous skin nodules

• Accumulation of ceramide

• Skeletal deformation

• cherry red macula

• ID

• fatal in early life