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

Chapter 24
Lysosomal Storage Diseases
Mark Haskins
Department of Pathology
School of Veterinary Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Urs Giger
School of Veterinary Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
I. LYSOSOMAL BIOLOGY
II. LYSOSOMAL STORAGE DISEASES (LSDs)
III. PATHOGENESIS
IV. CLINICAL SIGNS
V. DIAGNOSIS
VI. THERAPY
A. ER T
B. BM T
C. Gene Therapy
REFERENCES
I . LYSOSOMAL BIOLOGY
In 1955, de Duve et al. named the cytoplasmic particles that
contain a series of hydrolytic enzymes lytic bodies, or “ lysosomes.
” These organelles have a single lipoprotein membrane
and contain several dozen different acid hydrolase enzymes
( Holtzman, 1989 ), which typically catalyze catabolic reactions
A-B H 2 O → A - H B-OH, optimally at acid pH.
Lysosomes and their “ housekeeping ” enzymes degrade
many substrates that are found in all nucleated mammalian
cells. Deficiencies of these enzymes lead to lysosomal accumulation
of their substrates, thereby causing lysosomal storage
disease (LSDs), many of which have been discovered
and characterized in domestic animals.
In normal cells, most lysosomal hydrolases are synthesized
as preproenzymes on rough endoplasmic reticulum
(ER) ribosomes. Through a signal-recognition particle
complex, the enzymes are translocated into the lumen of
the ER where high mannose oligosaccharides are added
( Fig. 24-1 ; reviewed in Kornfeld and Sly [2001] ). These
oligosaccharides are trimmed, and the glycoprotein moves
to the Golgi apparatus where further shortening occurs.
Further posttranslational modification results from the
action of two enzymes that add a mannose 6-phosphate
(M6P) marker. Deficiency in activity of these transferases
can result in unique forms of LSD (e.g., mucolipidosis II
in domestic shorthair cats). The M6P moiety can be recognized
by two similar integral membrane glycoprotein
receptors, which transfer the enzyme to the lysosome.
These two receptors are (1) small and cation dependent
for binding and (2) large and cation independent, which
in some species also bind insulin-like growth factor II.
Both receptors appear responsible for the transport of the
enzymes from the Golgi apparatus via clathrin-coated vesicles
to the prelysosomal/endosomal compartment. Once
the lysosomal enzymes dissociate, the receptors recycle to
the Golgi apparatus.
A proportion of the M6P modified enzyme in the Golgi
may also leave the cell via secretory granules ( Fig. 24-1 ).
The secreted enzymes can then move from the extracellular
space into the circulation. Different enzymes appear to
be secreted from cells in varied amounts ( Dobrenis et al. ,
1994 ). Thus, the level of activity in serum of any particular
enzyme is related to how much is secreted and its stability
at plasma pH. Secreted enzymes can ultimately reach
the lysosome of other cells because the cation-independent
receptor is present in the plasma membrane on many cells
( Distler et al. , 1979 ; Kaplan et al. , 1977 ; Natowicz et al. ,
1979 ). Thus, enzymes that connect with this receptor can
be internalized and transferred to lysosomes. This pathway
provides the mechanism for therapy for lysosomal storage
diseases discussed later.
Although posttranslational glycosylation is common
to most lysosomal enzymes, other modifications or activator
proteins are necessary for the function of a subset
of the hydrolases. For example, the lysosomal sulfatases
(17 in humans; 14 in rodents) undergo an additional posttranslational
modification by sulfatase modifying factor
1 (SUMF-1), which converts a cysteine residue into
C (alpha)-formylglycine (FGly) at the active site ( Dierks
et al. , 2005 ; Preusser-Kunze et al. , 2005 ). The absence
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