The Role of Arrestins in Visual and Disease Processes of the Eye - Progress in Molecular Biology and Translational Science - page 250

metarhodopsin III form, in which the retinoid chromophore is more resis-
tant to reduction and thus continues to signal for a longer period. 55,106
7.2. Retinitis pigmentosa
In addition to Oguchi disease, some patients with defects in the arrestin1
gene present with a more progressive retinal degeneration known as retinitis
pigmentosa. 100,107-109 Curiously, these patients can have the same mutation
(adenine deletion at position 1147) common to many Oguchi patients who
simply develop stationary night blindness. The nature of this variable pen-
etrance is unclear but is a common feature of many eye diseases. Arrestin1
can also lead to retinitis pigmentosa if it forms stable complexes with
rhodopsin. This observation was first made in Drosophila , where stable
complexes of arrestin and rhodopsin led to severe forms of retinal degener-
ation. 110 The source of this degeneration appears to be twofold, resulting
from overwhelming of the endocytic machinery as well as signaling of an
apoptotic cascade through a guanine nucleotide-binding protein. 111 In ver-
tebrates, a similar retinal degeneration has been observed with mutants of
rhodopsin that are constitutively active and thus perpetually bound by
arrestin1. 112 In K296E rhodopsin mutants, the arrestin1-rhodopsin complex
mislocalizes to the inner segments and could trigger cell death via one of
several conceivable mechanisms, including excessive endocytosis, excess
proteasomal degradation, or activation of G-protein signaling pathway.
Experiments to distinguish between the potential mechanisms leading to
retinal degeneration have not been conducted.
7.3. Autoimmune diseases
In addition to retinal diseases, arrestin1 has also been implicated in several
autoimmune diseases. Circulating antibodies directed against arrestin1 have
been identified in both multiple sclerosis patients 113-115 and in patients suf-
fering from cancer-associated retinopathy. In patients with multiple sclero-
sis, it is not clear if there is a direct pathology of the myelin by these
autoantibodies. There is clear evidence, however, that arrestin1 leads to
T-cell activation 115 which has a defined role in the development of lesions
in multiple sclerosis. 116 Arrestin1 has also been implicated in cancer-
associated retinopathy. 117 In cancer-associated retinopathy, antibodies
typically develop against tumor antigens that either cross-react with retinal
proteins or are present in both the tumor tissue and retina, leading to retinal
degeneration. Arrestin1 is one of the common retinal proteins to which