Utility of the DHFR-based destabilizing domain across mouse models of retinal degeneration and aging

iScience

John D. Hulleman¹  Hui Peng¹  Shyamtanu Datta¹  Bogale Aredo¹  Bo Chen¹  Emi Nakahara¹  Steffi Daniel¹  Prerana Ramadurgum¹  DaNae R. Woodard¹  Marian Renwick¹  Rafael Ufret-Vincenty¹ 

[1] Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA;

关键词: Medicine;    Therapeutics;    Molecular biology;    Cell biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: The Escherichia coli dihydrofolate reductase (DHFR) destabilizing domain (DD) serves as a promising approach to conditionally regulate protein abundance in a variety of tissues. To test whether this approach could be effectively applied to a wide variety of aged and disease-related ocular mouse models, we evaluated the DHFR DD system in the eyes of aged mice (up to 24 months), a light-induced retinal degeneration (LIRD) model, and two genetic models of retinal degeneration (rd2 and Abca4−/− mice). The DHFR DD was effectively degraded in all model systems, including rd2 mice, which showed significant defects in chymotrypsin proteasomal activity. Moreover, trimethoprim (TMP) administration stabilized the DHFR DD in all mouse models. Thus, the DHFR DD-based approach allows for control of protein abundance in a variety of mouse models, laying the foundation to use this strategy for the conditional control of gene therapies to potentially treat multiple eye diseases.

【 授权许可】

Unknown