Lysosomal Storage Disorders Flashcards
What is a lysosome?
Small membranous bound organelles that contain more than 50 hydrolases required for degradation of macromolecules.
How can lysosomes break down molecules?
Macroautophagy
Endosomal degradation
Chaperone mediated autophagy
Microautophagy
How can you detect lysosomes?
Using antibodies against LAMP1 & 2 and LIMP1 or a lysotracker in live cells.
Define a Lysosomal Storage Disease (LSD)
Genetic lack of an enzyme or related protein leading to accumulation of undegraded substrates in lysosomes.
Can affect brain, bones/joints, muscles etc.
What is Mucopolysaccharide disease (MPS)?
Enzyme defect in breakdown of glycosaminoglycans (GAG).
Diff MPS = Diff GAG stored
Storage of DS or KS = bone or joint disease
Storage of HS = lysosomal swelling, neuroinflammation, severe brain dysfunction, behavioural problems.
Secondary storage and neuroinflammation = neurodegeneration
What are the characteristics of MPS l (Hurler’s Disease)?
Autosomal recessive inherited (1 in 100) Bone/joint problems, clawed hand, cloudy corneas, deafness, halted growth, heart valve problems Progressive neurodegeneration 100 mutations that cause Nonsense- severe form Missense- residual enzyme activity Splice- severe phenotype
What is MPS lll (Sanfilippo disease)?
1 in 700
Affects children in first decade of life, death in mid teens.
No treatment
Storage of HS and secondary GM and Neuroinflammation = neurodegradarion
75 mutations distributed over SGSH gene
How is HS degraded?
Proteoglycans are digested into HS chains in early endosomes by heparinises which are then directed to lysosomes.
Consequences of GAG stored within lysosomes
Cell swelling Dysfunction Cell killing pathways blocked Blockage of brain neurons Faulty joint development
Why is it important that GAG can be stored on cell surface?
They control how proteins on cell surface interact with other cells and proteins.
Excess GAGs are released into blood. How is this important?
Heparan sulphate mediates immune system- inflammation &a swelling in MPS brains
How do you diagnose LSD?
Early essential for early treatment Clinical assessment Detection of accumulated substrate Enzyme activity assay Genetic analysis
Describe the chromatography detection method.
GAG specific. May not reflect whole body burden of the disease, just renal function.
What are the treatment strategies for MPS?
Enzyme Replacement Therapy- delivered into bloodstream can be taken up by effected cells, BBB limits delivery to brain making it inefficient for neuropathic diseases.
Hematopoietic Stem Cell Transplant- delivery of enzymes from blood cells, monocytes traffic to brain and release.
Substrate Reduction Therapy- re routing degradation down alternate pathways
