Lecture 5 - Lysosomal storage disorders Flashcards
Lysosomes: (lysein/cleave + somos/body)
originally discovered by
de Duve in 1949
lysosomes are
Heterogeneous organelles containing specific hydrolases
Lysosomes allow
Allowing targeted degradation of proteins, but also nucleic acids, carbohydrates and lipids –> multitude of specific enzymes required
Lysosomes classification is based on
nature of stored material
Mucopolysaccaridoses, gangliosidoses, glycosphingolipid storage disorders and glycogen storage disorder
Diagnosis made by
Enzyme essays
Lysosomal biogenesis:
continuous process, ongoing synthesis of hydrolases, membrane constitutive proteins, new membranes
-High degree of control required
Lysosomes originate from
fusion of transgolgi network vesicles with late endosomes
Maturation process of lysosomes
with progressive acidification
a gradient from early endosomes: pH 6.2 to mature lysosomes: pH<5
Gradient facilitates
pH dependent dissociation of receptors and ligands and activates hydrolase function
What is essential for cellular function (in relation to the lysosomes)
- Accurate sorting, targeting and activation of lysosomal enzymes
(dysfunction at any step can lead to a lysosomal storage disorder)
complex oligosaccharide modifications during transit through Golgi
Cleavage of hydrophobic signal peptide in ER lumen as well as N-glycosilation
Lysosomal associated membrane proteins (LAMPS) are
sorted to the membrane or interior of lysosome
Phosphorylation, sulfatation, proteolytic processing and macromolecular assembly of heteromers occur concurrently
Pathogenesis of lysosomal storage disease
Accumulation of specific macromolecules within tissues and cells that have a high flux of these substrates (terminally differentiated, no division/dilution)
Not all cells are affected –> flux specific (example flux and traffic)
Majority of enzyme deficiencies result from
- point mutations at a locus encoding a single hydrolase
- All inherited as autosomal recessive
Threshold hypothesis:
Important for classification, pathophysiology and treatment
Implies a threshold of enzyme activity, below which disease develops
Small changes in enzyme activity near threshold can lead to or prevent disease
Defining enzyme activity thresholds:
useful for predicting dose-response relationships for treatment and evaluation of exogenous enzyme replacement therapy
Good cellular characterization within its unique microenvironment necessary
Accumulation of intermediates will cause
chaos in molecular trafficking –> a positive feedback loop is initiated (road blocks EVERYWHERE)
http://www.youtube.com/watch?v=y-uuk4Pr2i8
Mucopolysaccharidoses
Hurler disease
Gangliosidoses
Tay-Sachs disease
Mucopolysaccharidoses- Hurler disease
Deficiency of lysosomal enzymes needed for glycosaminoglycan catabolism (heparan-sulfate, dermatan sulfate etc)
Alpha-l-iduronidase defect
Accumulation causes: progressive mental retardation, skeletal abnormalities, corneal clouding, organomegaly (hepatosplenomegaly), joint stiffness, short stature, coarse facies
1:50 000-1:100 000
Typical leading to death in first decade
Treatment: comprehensive multisystem evaluation
Symptomatic: corneal transplantation, heart valve replacement
Enzyme replacement therapy under investigation
Gangliosidoses-Tay-Sachs disease
Defects in beta-hexosaminidase A, leading to its total deficiency
1 /30 Ashkenazi Jews (community along the Rhein river-Germany) is a carrier (screening recommended)
Infantile, juvenile and adult-onset variants
Accumulation of ganglioside
Gangliosidoses-Tay-Sachs disease
Infantile:
fatal neurodegenerative, macrocephaly, loss of motor skills, retinal cherry red spot, hyperacusis
Gangliosidoses-Tay-Sachs disease
Juvenile:
ataxia and dementia, death by age 10-15 years
Gangliosidoses-Tay-Sachs disease
Adult onset
clumsiness in childhood, progressive motor weakness
Thinking points
What does flux through the lysosomal system indicate?
Why can a change in the rate of fusion with autophagosomes affect disease onset?
What is the lysosomal pool size?
