Abstract
Purpose :
Inherited retinal diseases are caused by mutations in an unusually large number of genes. This makes them hard to study and treat. One of the approaches to overcome this complexity is to look for common pathobiological mechanisms unifying these diseases and to develop tools targeting these pathways. Our recent work revealed that proteasome overload, i.e. insufficient capacity of the ubiquitin-proteasome system to process misfolded or mistargeted proteins, is a common stress factor in several mouse models of retinitis pigmentosa (Lobanova ES, et al, PNAS, 2013). In this work we tested the hypothesis that an increase of proteasome activity in rods might serve as an approach to treat these blinding conditions.
Methods :
We generated two transgenic mouse lines overexpressing the components of proteasomal regulators specifically in rod photoreceptors. The first line overexpressed the PA28α protein, a component of the 11S regulator of proteasomal activity. The second line overexpressed PSMD11, a protein component of the 19S proteasome regulator. Each line was crossed with two mouse models of retinal degeneration to assess the effect of increased proteasomal activity on retinal degeneration rate. The first model was the knockout of rod transducin γ-subunit (Lobanova et al., J Neurosci, 2008). In this mouse, unpaired β-subunit of transducin cannot be properly folded in the absence of its cognate γ-subunit partner and is continuously targeted to proteasomes for degradation. In the second model (Sakami et al., J Biol Chem, 2011), one of the rhodopsin alleles is replaced by a dominant-negative mutant bearing the P23H point mutation. This causes destabilization of rhodopsin structure and its proteolytic degradation.
Results :
We have found that 30-40% increase in photoreceptor proteasomal activity is well-tolerated and does not cause any adverse effects on photoreceptor health. Furthermore, we observed that an increase in photoreceptor proteolytic capacity significantly delays the progression of retinal degeneration in two mouse models.
Conclusions :
Our data serves as proof of principle that an increase of photoreceptor proteolytic capacity is a promising approach for treating hereditary retinal degenerations and opens exciting opportunities for developing novel pharmaceutical approaches that manipulate proteostasis in affected cells.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.