Lysosomal storage diseases Flashcards
What are lysosomal storage diseases?
LSDs are a group of monogenic metabolic diseases involving or controlled by a single gene.
What mutations are involved?
Mutations in genes coding for particular enzymes (acid hydrolyses) and lysosomal membrane proteins.
How are LSDs classified?
LSD can be classified either by the substrate that accumulates or the gene that is mutated.
Describe the structure of the lysosome.
The lysosome is a spherical membrane-enclosed organelle.
What is the optimal pH of the lysosome and why?
The pH of the lysosome is 4.5-5, which is the optimal pH for hydrolases and is maintained by the proton pump ATPase/H+.
If the lysosome breaks down in the cell, the enzymes released do not act on intracellular components of the cells, since they are neutralised by the pH of the cytosol and rendered inactive.
This is why the pH is considered protective.
What are the main functions of the lysosome?
Endocytosis Autophagy Apoptosis UPR Interactions with mitochondria
How are lysosomes involved in endocytosis?
Internalisation of extracellular material.
Invagination of the plasma membrane and the formation of vesicles.
How are lysosomes involved in autophagy?
Destruction and recycling of damaged cellular material the body.
Involves the formation of autophagosomes.
Triggered by cell starvation.
How are lysosomes involved in apoptosis?
Programmed cell death.
Membrane of the lysosome becomes increasingly permeable.
Releases proteases in the cytosol including cysteine and cathepsin.
How are lysosomes involved in the unfolded protein response?
UPR - involves the removal of misfiled proteins and up-regulation of proteasomes and molecular chaperones involved in protein folding.
If these objectives are not achieved - apoptosis.
What interactions do lysosomes have with mitochondria and calcium signalling?
Cross talk between the lysosomes and mitochondria allows:
Degradation of dysfunctional mitochondria.
Maintenance of lysosomal function by acidification
Regulation of mitochondrial catabolism
Facilitation of calcium signalling which is involved in autophagy, membrane fusion and apoptosis.
How do lysosomes respond to specific protein mutations?
Enzyme mutations can lead to the accumulation of biomolecules.
Protein channel mutations can lead to the inappropriate transport of substances in the cellular environment.
Lysosomes are the main source of source damage from these mutations because aggregation usually occurs within the lysosome.
Give some characteristics of lysosomal dysfunction
Dysfunctional biosynthesis and catabolism of glycosphingolipids
Accumulation of substrates
Failed trafficking
Expansion of the lysosomal network and increased activity
Disturbed autophagy -membrane fusion and expansion
Disturbed calcium signalling and neurotoxicity
Apoptosis
Necroptosis – caspase independent cell death
Disruption of lipid raft
Macrophage activation
Complete disruption of the GSL (glycosphingolipid) pathway is incompatible with life.
True or false?
True
What is Krabbe disease?
Upregulation of metabolites from GAGs
Leads to the activation of receptors, secretion of cytokines, apoptotic signalling
GAGs are made elsewhere in the cells and their similarity to bacterial endotoxins activates immune response.
