Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 24 Lysosomal Storage Diseases
RER
LYSOSOME
FIGURE 24-1 Schematic diagram
of how lysosomal enzymes are processed
and delivered to the lysosome.
From Kornfeld, 1987 , with
permission.
P
P
Dol
GOLGI
ACIDIFIED COMPARTMENT
UDP-
UMP
P
P
P
P
P
P
Low pH
P
P
Secretory Protein
Lysosomal Enzyme
P
P
Secretory
Granule
Plasma Membrane
of this conversion results in multiple sulfatase deficiency.
A second factor, SUMF-2, which is also part of this system,
apparently down-regulates SUMF-1 activity ( Zito
et al. , 2005 ). The degradation of sphingolipids with short
hydrophilic head groups requires sphingolipid activator
proteins (SAPs), which are small, nonenzymatic glycoproteins
(reviewed in Sandhoff et al. , 2001 ). Deficiency in
activity of SAPs is also known to cause lysosomal storage
diseases.
Lysosomes degrade large complex substrates that have
been taken into a cell by endocytosis or autophagy (the
degradation/turnover of a cell’s own molecules). The endosome
containing the substrates fuses with a primary lysosome,
producing a secondary lysosome, which contains the
mixture of hydrolases and substrates. Degradation of most
substrates occurs by the activity of a cascade of hydrolases,
each step requiring the action of the previous hydrolase to
modify the substrate, thereby permitting catabolism to proceed
to the next enzyme step in the pathway. If one step
in the process fails, further degradation ceases. For example,
the glycosaminoglycans (GAGs), formerly known as
mucopolysaccharides, are long molecules of repeating subunits
and are, as part of proteoglycans, a component of the
ground substance of the extracellular matrix. Figure 24-2
illustrates the series of hydrolases that are responsible for
the sequential stepwise degradation of one of the glycosaminoglycans,
dermatan sulfate. Each of the enzymes in
this pathway has been described as deficient in a domestic
animal causing different mucopolysaccharidosis.
II . LYSOSOMAL STORAGE DISEASES
(LSDs)
The LSDs are defined as a group of individually rare
genetic disorders of cellular catabolism involving the lysosome.
The earliest detailed clinical reports of an LSD were
in humans by Tay (1881) and Sachs (1887) . Eight decades
later, the stored material in “ Tay-Sachs disease ” was defined
as GM2 ganglioside ( Svennerholm, 1962 ); 7 years later, the
enzyme that is deficient in activity (beta-hexosaminidase A)
was identified ( Okada and O’Brien, 1969 ; Sandhoff, 1969 ).
Isolation and sequencing of the cDNA coding for the alpha
subunit of beta-hexosaminidase A was reported 15 years
later ( Korneluk et al. , 1986 ; Myerowitz and Proia, 1984 )
and was quickly followed by the identification of the first
of more than 50 mutations responsible for Tay-Sachs disease
( Myerowitz and Hogikyan, 1986, 1987 ) and sequencing
of the entire gene ( Proia and Soravia, 1987 ). Similar
rapid progress has been made in identifying and characterizing
the molecular bases of all lysosomal diseases since
the 1980s.
LSDs are inherited as autosomal recessive traits (except
MPS II, which is X-linked) and result from mutations in
the coding sequence of one of the acid hydrolases located
in the lysosome. Point mutations, deletions, insertions, and
other alterations in sequence may occur anywhere along
the length of DNA coding the enzyme protein. Each individual
alteration will produce a unique change in the protein
affecting structure, stability, and function. Thus, these