Protein Misfolding and Cellular Stress: An Overview - Protein Misfolding and Cellular Stress in Disease and Aging - page 5

Oxidative
stress
Fig. 1. Simplified overview of the conception of the vicious cycle, comprising on one side
misfolded protein, either due to inherited genetic defects or oxidative damage, and on
the other, oxidative stress that - by oxidative damage - cause protein misfolding.
Accordingly, there exists a wealth of knowledge about the
antioxidant systems, such as glutathione, glutathione peroxidases
and reductases as well as superoxide dismutases, catalase and the
mentioned heme oxygenase, as the first line of defense, but also
about oxidatively modified proteins, which - if not eliminated - feed
into a vicious cycle of protein misfolding and further oxidation
(Fig. 1 ), eventually leading to cytotoxicity and cell death ( 9, 17-21 ).
In contrast to this large amount of knowledge about the gen-
eration, regulation, and effects of oxidative stress, the knowledge
about the mechanism(s), by which misfolded proteins in the cyto-
sol mediate the generation of oxidative stress, is currently very
limited. One mechanism, discussed in Chap. 2, concerns mis-
folded proteins, which form fibrils that may permeabilise mem-
branes and increase intracellular free calcium ions, which in turn
activate mitochondrial metabolic processes and production of
reactive oxygen species (ROS) as well as nitrogen oxide synthetase
(mtNOS), producing reactive nitrogen species (RNS) ( 22, 23 ).
This direct effect, which is associated with an effect on the mito-
chondria dynamics (see below and Chaps. 4 and 6), is probably
involved in the mechanism by which expanded CAG trinucleotide
repeats create oxidative stress in neuronal cells from patients with
Huntington's disease ( 24 ). Pertubation of the mitochondrial
dynamics seems also to be involved in a neuronal model of
Alzheimer's disease, where oxidative stress - paradoxically and as
yet unexplained - was associated with down-regulation of the
mitochondrial antioxidant superoxide dismutase (MnSOD) ( 25 ).
Another oxidative stress mediating mechanism, which may be
active in cases of fibril-forming misfolded proteins as well as in
cases of accumulated misfolded proteins in general, is overloading
and inhibition of the proteasome, which constitutes the main
cytosolic protease containing system. The proteasome is impor-
tant, both in normally functioning cells and in cells accumulating
misfolded/damaged proteins. It is noteworthy that oxidatively
modified proteins can be degraded directly by the proteasome,