Ophthalmology Update - Cleveland Clinic

Studies on Redox-Sensitive Retinal Proteins
Aim to Provide Clues for Strategies to Counter
Oxidative Stress
Although the pathophysiology of age-related
macular degeneration (AMD) remains
unclear, available evidence points to a role of
oxidative stress. Consistent with that concept,
results from the Age-Related Eye
Disease Study (AREDS) indicated a positive
effect of antioxidant therapy with high doses
of vitamins and minerals for reducing disease
progression in patients with advanced AMD.
research being conducted by george hoppe, m.d.,
ph.d., and Jonathan sears, m.d., at the cole eye institute
is aiming to gain insight into the endogenous
antioxidant protective mechanisms in the retina with
the hope that information may ultimately be used to
design more effective antioxidant interventions.
“Understanding of the molecular basis for the antioxidant
mechanisms in the retina could allow us
to develop more targeted therapies that could induce
or facilitate their function. in current clinical use,
antioxidant treatment involves administration of
high doses and yields only a modest benefit. We
believe that therapeutic efficiency could be enhanced
by more precise elucidation of the molecular basis
for antioxidant mechanisms,” says dr. hoppe.
his research is focusing on characterizing redoxsensitive
proteins and the changes they undergo in
response to oxidative stress, and in particular determining
proteins that undergo redox-dependent
interactions with glutathione, a ubiquitous peptide
anti-oxidant.
“Oxidative modifications of cysteine residues on proteins
is a potent way of regulating protein function,
and when there is a redox shift toward oxidative
potential, glutathione tends to bond covalently with
the sulfhydryl moieties on proteins and this in turn
results in changes in protein conformation and
activity,” he explains.
so far, drs. hoppe and sears have identified two proteins
that appear to mediate retinal adaptation to a
high oxidative environment. the chaperone heat
shock cognate protein 70 (hsc70) is one of those
FIGURE 1
FIGURE 2
proteins, and their studies show that as a result of
interactions with glutathione during oxidation,
hsc70 increases its chaperone activity and becomes
more protective.
“another interesting finding is that this increase
in hsc70 chaperone activity occurs as an atp-independent
process. that suggests this protein can
adapt to conditions of high oxidative stress where
atp concentration is reduced by forming disulfide
bonds with glutathione,” dr. sears says.
the nuclear transcription factor high mobility group
protein B1 (hmgB1) is a second protein that they
have identified as being redox-sensitive. hmgB1,
which also has dna chaperone-like properties, has
been shown to be modified by glutathione with
resultant changes in its chaperone activity. most
Continued on page 8
i n v e s t i g a t i O n s
Figure 1: Expression of HmgB1
in the retina is seen in green
and red.
Figure 2: A three-dimensional
model of HmgB1 molecule
interacting with DNA.
c O l e e y e i n s t i t U t e c l e v e l a n d c l i n i c . O r g / e y e //