Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia

Area of Science:

• Ophthalmology
• Genetics
• Cell Biology

Background:

• Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy impacting photoreceptors, retinal pigment epithelium (RPE), and choroid.
• Caused by mutations in the CHM gene, CHM results in deficiency of Rab escort protein 1 (REP1), crucial for intracellular trafficking.
• Currently, no approved therapies exist for CHM, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To investigate the roles of oxidative and endoplasmic reticulum (ER) stress in CHM pathogenesis.
• To screen for neuroprotective agents capable of mitigating these stress pathways in CHM models.

Main Methods:

• Examined oxidative and ER stress markers in CHM zebrafish and patient-derived fibroblasts.
• Assessed the expression of key stress-related genes, including txn, cat, sod3a, bip, atf4, atf6, SOD2, and CHOP.
• Screened neuroprotectants for their efficacy in reducing cellular stress.

Main Results:

• Dysregulated expression of oxidative stress markers (txn, cat, sod3a) and ER stress markers (bip, atf4, atf6) was observed in CHM zebrafish.
• CHM fibroblasts showed reduced SOD2 expression, diminished BIP levels, and increased CHOP expression.
• REP1 deficiency was linked to impaired vesicular trafficking, photoreceptor outer segment phagocytosis, and melanosome transport, leading to retinal and RPE stress.

Conclusions:

• Oxidative and ER stress are implicated in the pathophysiology of Choroideremia.
• Defects in REP1 function contribute to cellular stress within the retina and RPE.
• Targeting oxidative and ER stress pathways presents a promising therapeutic approach for CHM.