Lecture 5 Flashcards
(42 cards)
What type of diseases are lysosomal storage diseases?
Autosomal recessive diseases, around 45, and one X linked
What causes the diseases?
Defects in substrate degradation in the lysosome, trafficking to the lysosome and biogenesis of the lysosome. Build up of substrate leads to swollen lysosomes.
What is a lysosome?
Subcellular electron dense organelle, filled with 70 hydrolytic enzymes, enough to break down all biological macromolecules, low pH (~4), membrane bound, destination for material from endocytosis and autophagy. Enzymes are trafficked to lysosome via M6P receptor pathway
Which cell types have additional burden on their lysosomes?
Professional phagocytes; macrophages and neturophils
How is endocytosis different in the nervous system?
Endocytosis that occurs in synapse and the axon requires the cargo to be carried back up to the cell body where the lysosomes are
Oultine the M6P pathway
Mannose-6-phosphate group added via N-linked oligosaccharides as they moved through cis-golgi. M6P recognised by M6P-receptor in trans-golgi and delivers them to the late endosome. Lower pH causes dissociation. M6PR are trafficked back to trans-golgi for re-use. M6P also stops the hydrolyases from working before in the lysosome.
What is the general cellular phenotype?
Swollen, multilamellar, osmiophilic endomsomes/ lysosomes. Accumulation of lipofuscin/ceroid. Excessive synaptogenesis/dendritogenesis. Shrinkage of the CNS. Mistrafficking of cholesterol
How can lipofuscin be seen?
Autofluorescence
What are mucopolysaccharides?
Long unbranched structures containing disaccharide units. High viscosity and rigidity. Excellent lubricators and shock absorbers. Important component of cell membranes.
What is the phenotype of Sanfilippo syndrome?
Four types, but all have an inability to breakdown heparan sulphate. Mental retardation, joint stiffness, coarse features, death in middle teens.
What is the most common Mucopolysaccaridosis?
Sanfilippo Syndrome
How is Sanfilippo syndrome diagnosed?
GAGs in urine
WBC enzyme assay or plasma enzyme assay
Why is the activity of mutated hydrolyases of lysosomal storage diseases zero, even though the mutations are not complete function knock outs?
The mutation causes misfolding, so even though the enzyme could function if it reached to lysosome, it is degraded via ERAD long before this happens.
How can the ERAD system be overcome?
Chaperone therapy, provides sugar or mimetic that the enzyme usually encounters and causes the enzyme to fold more accurately and hence avoid ERAD
What are the symptoms of Mucolipidosis-II?
Developmental delay, psychomotor deterioration, dysmorphia, death in early childhood.
What causes Mucolipidosis-II?
Loss of N-acetylglucosaminyl-1-phosphotransferase. Involved in adding phosphate group to mannose-6, and hence delivering hydrolyases to the lysosome
Which population shows a high occurrence of Mucolipidosis-IV?
Ashkenazim Jewish population - 1/90 to 1/100
How has this high incidence been explained, in theory?
Being heterozygous confers an immunity to tuberculosis, a balancing mutation, as the tuberculosis bacterium resides in the lysosome (never proven)
What are the symptoms of Mucolipidosis-IV?
Psychomotor retardationk, corneal opacity, retinal degeneration, iron deficiency and improper stomach pH
What causes Mucolipidosis-IV?
Defect in Mucolipin-1, a TRP channel involved in Fe2+ efflux from the lysosome
Which tissue type are sphingolipids a major component of?
Name three
Neural Tissue
Ceramide
Sphyingomyelin
Glycoshingolipids
What roles do sphingolipids play?
Trafficking, apoptosis, proliferation and stress
What are sphingolipids tightly associated with?
Cholesterol
Where are sphingolipids trafficked?
Down from membrane during endocytosis, then recycled back to membrane vis the trans-golgi network. Very few make it to the lysosome
