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This aggregated material can afterward be chemically further modified
by a great variety of cellular metabolites, including aldehydic lipid peroxida-
tion products (255, 299, 350). Bifunctional aldehydes, like 4-hydroxy-nonenal
or malondialdehyde, are able to form covalent cross-links (255, 350). This
material might undergo further reactions and form the “age pigment,” the
“lipofuscin,” also called “AGE-pigment-like fluorophores” by various authors
(351, 352). The formed aggregates comprise a major part of the cellular
hydrophobic phase as demonstrated by costaining with the lipophilic dye
ANEPPS (4-[2-[6-(dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-
pyridinium, inner salt). The involvement of free radicals and cross-linking
reactions by aldehydic lipid peroxidation products or carbohydrates have been
postulated by several groups as one of the initial steps in the formation of
fluorescent oxidized/cross-linked aggregates (299, 353-355). The occurrence of
protein aggregates in cells may trigger a number of intracellular reactions,
including the fact that the aggregates might act to promote cell death. Most
protein aggregates are ubiquitinylated and the accumulation of intracellular
ubiquitin conjugates leads to cell cycle arrest (356). Furthermore, while the
proteasomal system is inhibited by aggregates, regulatory proteins and tran-
scription factors cannot be degraded in time, and thus may initiate the apop-
tosis pathway (357). Therefore, disturbance in the normal level of certain
proteins can cause the induction of apoptosis. The question of the relationship
between proteasome inhibition and protein aggregates was raised in a number
of studies (358-360). We have reported that heavily oxidized and cross-linked
proteins are poor substrates for the proteasome. More than that, these aggre-
gates are able to inhibit the proteasome as shown by us (361) and by others
(255, 350).
Furthermore, the proteasome activity drastically declines in cells fed with
aggregated/oxidized proteins (361). Proteins covalently aggregated with cross-
linkers, such as HNE, are also able to inhibit the proteasome (255, 350). We
were able to demonstrate that HNE cross-linked amyloid
peptide, which
forms the senile plaques of Alzheimer's disease, is able to inhibit the protea-
some (289). Whereas, in our hands, neither the amyloid peptide nor HNE alone
(up to 100
β
M) was able to affect proteasomal activity. The high-molecular-
weight amyloid peptide HNE aggregates were effective inhibitors of the pro-
teasome. Mutated proteins tending to aggregation are also able to inhibit the
proteasome, such as the mutant ataxin-1 (362) or the huntingtin protein with
an expanded polyglutamine repeat (363). Proteins must be deaggregated and
unfolded in order to be able to enter the 20S proteasome and reach the active
β
μ
subunit proteolytic centers located in the inner chamber of the hollow cyl-
inder. Most aggregated proteins, particularly cross-linked aggregates, may
no longer “fit” into the proteasome. The cross-linking of these proteins may
thus result in restricted entry into the core particle of the proteasome and
incomplete degradation. According to the “bite and chew model” proposed in
Reference 331, the proteasome loses its proteolytic power if it is clogged up
by nondegradable material.
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