Environmental Engineering Reference
In-Depth Information
Lysosomes function as the digestive system of the cell; these organelles are
capable of breaking down large complex molecules — proteins, nucleic acids,
carbohydrates and lipids — into smaller, simpler components that can be reused
by the cell for a while, then degraded and recycled. The recycling process carried
out by lysosomes thus enables the body
s cells to function normally. When degra-
dation and recycling processes fail, there are a number of problems due to accu-
mulation and storage within lysosomes of the materials ready for breakdown. When
the accumulated amount is very high, it inhibits the catabolic enzymes and perme-
ases that are not genetically deficient, leading to secondary substrate accumulation
[
39
,
40
]. Therefore, the diseases caused by such disruption of normal functioning
are called “lysosomal storage diseases.” Although the lysosome have been discov-
ered only 5-6 decades ago, the first description of a lysosomal storage disease was
in 1881 for Tay-Sachs disease, followed in 1882 by the description of Gaucher
disease and in 1898 of the Fabry disease, though at that moment it was not clear that
the various diseases share the common feature of lysosomal storage. This scientific
breakthrough represented the starting point for investigations and discoveries in
terms of the intracellular biology of these enzymes and their substrate and also in
understanding the pathophysiological basis of the lysosomal storage diseases
(LSDs).
LSDs comprise a heterogeneous group of more than 50 inherited genetic dis-
eases characterized by mutations in gene that encode mainly lysosomal hydrolases
[
41
], but also some lysosome membrane proteins or other proteins involved in the
processing, trafficking and targeting [
42
]. As a consequence, significant decrease
(
'
10 % normal levels) or a complete absence in the activity of a soluble lysosomal
enzyme is noticed. The common feature for all LSDs is the initial inappropriate
accumulation of specific macromolecular substrates inside organelles of the
endosomal-autophagic-lysosomal system, which disrupts the normal functioning
of the cell, leading to cell dysfunction and clinical abnormalities specific for LSDs
and ultimately, premature death.
The most common lysosomal storage disease classification is according to the
nature of the major compound accumulated. Large classes of LSD correspond to
mucopolysaccharidoses (MPS), sphingolipidoses, mucolipidoses, glycopro-
teinoses, oligosaccharidoses, and glycogen storage diseases. Although the absence
and/or the deficiency of a lysosomal enzyme activity represent the common basic
pathogenesis for this class of congenital diseases, it is not possible to generalize
LSD symptoms. Even within a single disease, the clinical manifestations vary
depending on the amount of the accumulated substrate; as the latter is higher, the
number and cell types affected by storage are greater, so that nearly every bodily
system is affected ultimately.
Patients with LSDs appear normal at birth and become symptomatic over the
first 3-6 months or even years of life. Several disorders, including Pompe,
Tay-Sachs, Gaucher, may exist in three forms, infantile, juvenile and adult. The
speed and severity of the evolving symptoms depends on the basic disease and the
value of the residual enzymatic activity. As a general trait, infantile form charac-
terized by earlier onset of symptoms arising from brain pathology represents the
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