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

Hui Peng, Prerana Ramadurgum, Da Nae R. Woodard, Steffi Daniel, Emi Nakahara, Marian Renwick, Bogale Aredo, Shyamtanu Datta, Bo Chen, Rafael Ufret-Vincenty, John D. Hulleman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number104206
JournaliScience
Volume25
Issue number5
DOIs
StatePublished - May 20 2022
Externally publishedYes

Bibliographical note

Funding Information:
D.R.W. was supported by a National Eye Institute (NEI) Diversity Supplement ( EY027785 ). J.D.H. was supported by an endowment from the Roger and Dorothy Hirl Research Fund, a Macular Degeneration Research Grant from the BrightFocus Foundation ( M2018099 ), a NEI R21 Grant ( EY028261 ), and a Career Development Award from Research to Prevent Blindness (RPB). Additional support was provided by a NEI Visual Science Core Grant ( P30 EY030413 ) and an unrestricted grant from RPB (both to the UT Southwestern Department of Ophthalmology). We would like to thank Dr. Katherine Wert (UT Southwestern) for her assistance with subretinal injections.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Cell biology
  • Medicine
  • Molecular biology
  • Therapeutics

PubMed: MeSH publication types

  • Journal Article

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