Lecture 5 - Lysosomal storage disorders

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Lysosomes: (lysein/cleave + somos/body)
originally discovered by

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de Duve in 1949

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lysosomes are

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Heterogeneous organelles containing specific hydrolases

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Lysosomes allow

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Allowing targeted degradation of proteins, but also nucleic acids, carbohydrates and lipids –> multitude of specific enzymes required

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Lysosomes classification is based on

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nature of stored material

Mucopolysaccaridoses, gangliosidoses, glycosphingolipid storage disorders and glycogen storage disorder

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Diagnosis made by

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Enzyme essays

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Lysosomal biogenesis:

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continuous process, ongoing synthesis of hydrolases, membrane constitutive proteins, new membranes

-High degree of control required

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Lysosomes originate from

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fusion of transgolgi network vesicles with late endosomes

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Maturation process of lysosomes

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with progressive acidification
a gradient from early endosomes: pH 6.2 to mature lysosomes: pH<5

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Gradient facilitates

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pH dependent dissociation of receptors and ligands and activates hydrolase function

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What is essential for cellular function (in relation to the lysosomes)

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• Accurate sorting, targeting and activation of lysosomal enzymes
  (dysfunction at any step can lead to a lysosomal storage disorder)

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complex oligosaccharide modifications during transit through Golgi

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Cleavage of hydrophobic signal peptide in ER lumen as well as N-glycosilation

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Lysosomal associated membrane proteins (LAMPS) are

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sorted to the membrane or interior of lysosome

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Phosphorylation, sulfatation, proteolytic processing and macromolecular assembly of heteromers occur concurrently

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Pathogenesis of lysosomal storage disease

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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)

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Majority of enzyme deficiencies result from

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• point mutations at a locus encoding a single hydrolase
• All inherited as autosomal recessive

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Threshold hypothesis:

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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

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Defining enzyme activity thresholds:

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useful for predicting dose-response relationships for treatment and evaluation of exogenous enzyme replacement therapy
Good cellular characterization within its unique microenvironment necessary

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Accumulation of intermediates will cause

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chaos in molecular trafficking –> a positive feedback loop is initiated (road blocks EVERYWHERE)

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http://www.youtube.com/watch?v=y-uuk4Pr2i8

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Mucopolysaccharidoses

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Hurler disease

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Gangliosidoses

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Tay-Sachs disease

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Mucopolysaccharidoses- Hurler disease

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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

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Gangliosidoses-Tay-Sachs disease

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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

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Gangliosidoses-Tay-Sachs disease Infantile:

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fatal neurodegenerative, macrocephaly, loss of motor skills, retinal cherry red spot, hyperacusis

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Gangliosidoses-Tay-Sachs disease Juvenile:

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ataxia and dementia, death by age 10-15 years

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Gangliosidoses-Tay-Sachs disease Adult onset

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clumsiness in childhood, progressive motor weakness

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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?