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Researchers show how proteasome modification may provide a therapeutic strategy to dealing with dominant-negative retinitis pigmentosa (RP).

Researchers, based at the Department of Ophthalmology, Duke University School of Medicine, have shown how modification of the proteasome in photoreceptor cells may be used to enhance the disposal of mis-folded or mis-targeted protein. Ridding retinal cells of such dysfunctional protetins has the potential to bring about therapeutic benefit to patients suffering ocular disorders such as retinitis pigmentoasa (RP). The research, published in Nature Communications (DOI: 10.1038/s41467-018-04117-8), indicates that stimulation of proteasome mediated protein degradation may present a therapeutic approach to treating a range of disorders in which mis-folded proteins contribute to a significant part of the pathology.


Proteasomes are sub-cellular molecular “machines” that function in the degradation of unwanted or mis-folded proteins through a process of proteolysis, essentially acting as the recycling waste system of cells. In a range of disorders, mis-targeted or mis-folded proteins need to be removed from the cell to avoid clogging up the system leading to complete cell dysfunction. In a disorder such as dominant-negative retinitis pigmentosa, a mutation in one allele of the rhodopsin gene can cause the corresponding protein to mis-fold and negatively impact on the normal protein. While the proteasome might diligently process and dispose of the mis-folded proteins, the rate at which it does so may not be sufficient to beneficially alter the ratio of normal to mis-folded protein, ultimately leading to the pathology. However, if proteasome activity could be speeded up, just by enough to alter the normal:mis-folded ratio positively, then the result could delay the pathology and provide meaningful sight for a much longer period of time.


In the Duke University research, the team used mouse models of RP in which they engineered over-expression of a particular sub-unit of the proteasome – the PA28α subunit of the 11S proteasome cap. Over-expression of this sub-unit was shown to support photoreceptor cell survival in degenerating retinas and demonstrated a convincing effect in models of one of the most common forms of RP in the human population. In the Pro23His animal model, with one copy of the mutant rhodopsin gene, modifying the proteasome activity resulted in a quadrupling of the number of surviving photoreceptors in the inferior retina of 6-month-old mice. These results indicate that the approach represents a viable therapeutic strategy and, significantly, the approach is entirely independent of the mutation or affected gene. Given the estimated 4,500 mutations occurring in more than 250 genes that lead to hereditary blindness, such a proteasome modification strategy may represent an efficient and attractive approach to dealing with a disorder characterized by seemingly unwieldy heterogeneity.