Role of Proteasome Overload in Pathogenesis of Retinitis Pigmentosa

PROJECT SUMMARY / ABSTRACT
Retinitis pigmentosa (RP) is the most common hereditary cause of blindness, affecting over 1.5 million
people worldwide. RP has an extraordinarily variable etiology, with over 5,000 distinct mutations in more than
300 genes implicated in its pathogenesis, which suggests that the most productive therapeutic interventions
would employ gene-independent strategies to target the cellular pathology shared across many mutations and
patient groups. Our lab has demonstrated that one such common pathology is the impairment of cellular
proteostasis. This condition arises from the insufficient capacity of the ubiquitin-proteasome system to process
large amounts of misfolded or mistargeted mutant proteins. Reducing this stress by enhancing ubiquitin-
independent protein degradation causes a major delay in the degeneration of photoreceptors bearing the P23H
rhodopsin mutation, a commonly encountered cause of human RP. We propose to expand the mechanistic
investigation of proteostatic imbalance in mouse models of photoreceptor degeneration and plan to further
explore practical approaches for restoration of proteostatic equilibrium. Our overarching goal is to identify
optimal therapeutic strategies and drug targets that could be used to ameliorate these devastating blinding
conditions.
We will investigate whether enhancement of proteasomal activity achieved by directly targeting the 20S
proteasome core can alleviate retinal degeneration in mouse RP models. Progression of photoreceptor
degeneration in mouse models of RP can be considerably delayed by overexpressing the 11S regulatory cap,
which facilitates the accessibility of protein substrates to the proteolytic sites located inside the 20S core. We
propose to address whether a similar therapeutic effect could be achieved through direct manipulation of the
20S core by two complementary approaches – genetic and pharmacologic. The therapeutic effects of these
strategies will be assessed in two mouse models of RP of dissimilar etiology – rhodopsin P23H mutation and
the BBS4 knockout – and will include retinal histological analysis, electroretinography, and optomotor
responses.
The results of these experiments will demonstrate whether direct activation of 20S proteasomes can serve
as a therapeutic strategy to treat inherited blindness. These data will encourage further investigations of
proteasome activity enhancers and ultimately advancement to clinical trials for RP. Furthermore, promising
results in RP models will encourage the evaluation of these drugs in models of other retinal degenerations and
potentially neurodegenerative diseases, all of which exhibit proteostatic stress as a pathophysiological feature.

Grant Number: 5K08EY033857-04
NIH Institute/Center: NIH
Principal Investigator: Oleg Alekseev