Dominant and recessive mutations in rhodopsin activate different cell death pathways

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Mutations in the rhodopsin (RHO) gene are a frequent cause of inherited retinal dystrophies.
• Both dominant and recessive RHO mutations lead to similar clinical symptoms but may involve different molecular mechanisms of retinal degeneration.
• Understanding these distinct pathways is crucial for developing targeted therapies.

Purpose of the Study:

• To characterize the molecular mechanisms of photoreceptor degeneration in murine models of RHO-linked retinal dystrophy.
• To investigate the efficacy of targeting specific cell death pathways, calpain and ER-stress, in different RHO mutation models.

Main Methods:

• Characterization of three murine models: Rho loss-of-function and dominant P23H RHO mutation.
• Analysis of photoreceptor cell death pathways, including calpain activation and apoptosis-inducing factor (Aif).
• Assessment of ER-stress responses.
• In vivo treatment with calpastatin (calpain inhibitor) and salubrinal (ER-stress inhibitor).

Main Results:

• Rho loss-of-function models showed activation of calpain and Aif in dying photoreceptors.
• Dominant P23H RHO mutation models activated both calpain-Aif and ER-stress pathways.
• Calpastatin was neuroprotective in Rho loss-of-function models, while salubrinal was more effective in P23H RHO models.
• Combined treatment with calpastatin and salubrinal further reduced photoreceptor cell death in dominant mutation models.

Conclusions:

• Rho loss-of-function and dominant P23H RHO mutations trigger distinct molecular pathways leading to photoreceptor degeneration.
• Targeting calpain is effective for loss-of-function mutations, whereas targeting ER-stress is more beneficial for dominant P23H mutations.
• Dominant RHO mutations likely involve co-activation of calpain and ER-stress dependent cell death pathways.