Relative quantification of (phospho)proteoforms reveals important common disease pathways in Retinitis pigmentosa mouse models

Introduction

Inherited retinal degenerative diseases (IRDs) affect approximately 1 in 2000 worldwide, leading to significant blindness among young and working-age people due to a lack of effective treatments ^1,2. Retinitis pigmentosa (RP) is one major subtype of IRD arises from over 150 identified mutations ³. Targeting each specific mutation with gene therapy is unfeasible, so broader disease-modifying treatments offer a potential strategy to halt disease progression. The aim of the study is to find common drug targets in highly translationally relevant mouse models of RP such as Pde6β^Rd10 (rd10) and Rho^P23H/WT (P23H).

Results

Using LC-MS and label-free protein quantification ^4,5, over 7000 proteins were quantified, with 600 common differentially expressed in rd10 and P23H models, implicating approximately 90 KEGG pathways. Notably, nucleotide metabolism and cAMP signaling pathways emerge as significant drug targets alongside the well-known cGMP pathway in retinal degenerative diseases ⁶. Moreover, in the rd10 mouse model, over 26,000 phosphorylation sites were identified and quantified. Following the normalization of phosphorylation levels to protein abundance, the sites were refined to feature those with a ratio exceeding 1.5 or falling below 0.5. Dephosphorylation was predominant, notably in proteins that regulate phototransduction and cGMP binding including GRK1, RHO, PDC, SLC24A1 & TULP1, as well as in those that play a role in nucleotide metabolism such as DNM3, HSPA1A, SERBP1, and HSP90AB1.

Conclusion:

Although the rod photoreceptors die via distinct pathways in the phosphodiesterase (rd10 model) and rhodopsin (P23H model) associated RP models, the downstream proteomic changes are largely convergent. Targeting some of these shared downstream pathways in RD could offer a unified treatment approach for retinal degenerative diseases caused by idiopathic factors or multiple genetic mutations, such as RP.

References:

1)doi.org/10.1016/j.preteyeres.2010.03.004

2)doi.org/10.1080/13816810.2021.1913610

3)doi.org/10.1016/j.preteyeres.2017.10.00

4)doi.org/10.1074/mcp.M113.031591

5)doi.org/10.1038/s41592-019-0638-x

6)doi.org/10.1073/pnas.1718792115