Escolar Documentos
Profissional Documentos
Cultura Documentos
Module 755
The Brain in Health and Disease
Sean Sweeney
The Lysosome
subcellular electron dense organelle
filled with c.a. 70 hydrolytic enzymes: will break down all
biological macromolecules
low pH (~4.0), membrane bound
Considered the gut or garbage disposal unit of cell
Material for degradation trafficked to lysosome via endocytosis
or autophagy
Lysosomal enzymes trafficked to lysosome via M6P receptor
pathway
QuickTime and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Mistrafficking of cholesterol
(cholesterol recycling?)
Classification :
Mucopolysaccharidoses (variable nervous system involvement)
Mucolipidoses (originally considered an MPS)
Glycoproteinoses
Glycogen storage
Sphingolipidoses
Lipid storage disorders
Multiple enzyme defects
Transport defects
Batten Disease
(Red = nervous system involvement)
Mucopolysaccharides
Defective metabolism and accumulation of GAGs
Most abundant polysaccharides
Long unbranchedstructure containing
disaccharide units:
High viscosity + rigidity
Excellent lubricators and shock absorbers
Important component of cell membranes
QuickTime and a
TIFF (LZW) decompressor
are needed to see this picture.
Mucopolysaccharidoses:
Enzyme Defective
STRUCTURE
OH
CH2O
microdomains (?)
trafficking
NH
O
SIGNALLING
Sphingomyelin
O
OH
CH2O
NH
CH3
O
(CH2)2 N+
CH3
O-
Glycosphingolipids
OH
CH2O
NH
O
Glc
CH3
Apoptosis
proliferation
stress
- Sphingomyelin
- Ceramide
- Sphingosine
- Sphingosine-1-phosphate
- Cerebrosides
- Gangliosides
Sphingolipids are
tightly associated with
cholesterol
QuickTime and a
TIFF (Uncompres s ed) decompres s or
are needed to s ee this picture.
Batten disease
QuickTime and a
TIFF (LZW) decompressor
are needed to see this picture.
Batten (1903)
Locus
Disease
Protein deficiency
Function
CLN1
infantile NCL
de-palmitoylation
Lysosome
CLN2
tripeptidyl peptidase
protease
lysosome
CLN3
juvenile NCL
transmembrane protein
?
lysosome
CLN4
adult (Kufs)
Not identified
CLN5
transmembrane protein
CLN6
CLN7
CLN8
EPMR
transmembrane protein
ER, ER/Golgi
CTSD
Ovine NCL
cathepsin D
protease
lysosome
?
LE/lysosome
ER protein
QuickTime and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Treatment:
BMT (membrane proteins)
enzyme replacement (BBB?)
gene therapy
substrate reduction- Miglustat (monosaccharide
mimetic-imino sugar)
Neuronal stem cells (membrane proteins?)
Chemical chaperone therapy
Neuroinflammation
Economic cost
ERT is current most effective treatment (non neurodegenerative LSDs):
Disease
Treatment
Gaucher
ERT
145,000 - 290,000
Gaucher
SRT
91,000
Fabry
ERT
156,000
Hurler-Scheie (MPS-I)
ERT
340,000
Maroteaux-Lamy (MPS-VI)
ERT
377,000
Reasons:
High regulatory costs
Cost of research
Lack of competition (Orphan Drug Act 1983, US)
http://132.236.112.18/fruitfly/shaker/physiology/
spinster
suppresses
synaptic growth
spinster mutants
have a shortened
lifespan
4 transcripts = 12 TM domains
1 transcript = 8 TM domains
WT
filipin
spin4/spin5
spinster identifies a novel component of the late endosome/lysosome that when mutated gives
rise to all of the hallmarks of lysosomal storage disease
spinster potentially identifies a signalling pathway driving synaptic overgrowth
Summary
Lysosomal storage disease are caused by defects in lysosomal hydrolases and proteins
essential to lysosomal biogenesis/function
LSD lysosomal defects give rise to swollen lysosomes, developmental and degenerative
defects with varying involvement of the nervous system due to storage of material
in the lysosome.
Lysosomal storage diseases identify proteins essential to lysosomal function
LSDs cause death in childhood (generally) after normal infancy
LSDs are essentially incurable, but some are treatable to varying degrees.
Model organisms are helping to define the biology of the LSDs, in particular the
pathogenic cascade