In vivo phenotypic and molecular characterization of retinal degeneration in mouse models of three ciliopathies

Area of Science:

• Cell Biology
• Genetics
• Ophthalmology

Background:

• Cilia are vital organelles; defects cause ciliopathies, leading to clinical features like retinal degeneration (RD).
• Understanding RD mechanisms in ciliopathies is crucial for developing therapeutic strategies.
• Bardet-Biedl Syndrome (BBS), Alström Syndrome (ALMS), and Leber Congenital Amaurosis (LCA) are key ciliopathies affecting vision.

Purpose of the Study:

• To compare the underlying mechanisms and disease progression kinetics of retinal degeneration in three distinct ciliopathy mouse models.
• To identify potential therapeutic targets by analyzing pathological pathways driving RD.
• To investigate the role of rhodopsin mislocalization and Endoplasmic Reticulum (ER) stress in ciliopathy-associated RD.

Main Methods:

• Scotopic electroretinography (ERG) to assess retinal function in mouse models.
• Transmission Electron Microscopy (TEM) to evaluate retinal structural integrity.
• Real-time PCR to monitor apoptotic Caspase-related pathways and gene expression.

Main Results:

• Bardet-Biedl Syndrome (BBS) and CEP290-mediated LCA models exhibit perinatal RD with rhodopsin mislocalization and ER stress.
• Alström Syndrome (ALMS) model displays a slower degeneration phenotype, lacking rhodopsin mislocalization and ER stress.
• Distinct pathological pathways and disease progression rates were observed across the studied ciliopathy models.

Conclusions:

• Ciliopathies, despite shared vision loss, exhibit diverse mechanisms and kinetics of retinal degeneration.
• Rhodopsin mislocalization and ER stress are key pathological features in specific ciliopathies like BBS and LCA.
• The findings highlight the need for tailored therapeutic approaches based on the specific ciliopathy and its underlying pathology.