Mitochondrial dysfunction in retinal degeneration-a pilot study based on the model of inherited optic atrophy- A Novel Mouse Model for Autosomal Dominant Optic Atrophy

Abstract

Purpose : The purpose of this study was to develop a mouse model for Autosomal Dominant Optic Atrophy (ADOA), a genetic condition caused by mutations in the Opa1 gene. The aim was to create a model that accurately replicates the disease seen in human patients with ADOA. This mouse model would serve as a valuable tool for investigating the underlying mechanisms of the disease and testing potential gene therapies or treatments.

Methods : The methods involved the generation of an Opa1 knock-in mouse model with patient-specific mutations. Heterozygous Opa1 mutant mice were chosen for study, as homozygous mutations are lethal. Over time, these mutant mice were observed to exhibit progressive dysfunction of retinal ganglion cells (RGCs), which closely resembled the clinical presentation of ADOA in humans. Various techniques were employed to assess this dysfunction, including immunohistochemical staining, pattern electroretinogram measurements, and spectral domain optical coherence tomography. Additionally, the researchers used transmission electron microscopy to examine the structural abnormalities within the mitochondria of Opa1 mutant mice.

Results : The heterozygous Opa1 mutant mice exhibited a gradual and statistically significant loss of RGCs (P < 0.05), providing robust evidence of disease progression. Furthermore, functional assessments, such as reduced pattern electroretinogram amplitudes and diminished retinal nerve fiber layer thickness (P < 0.05), confirmed the presence of functional deficits similar to those observed in human ADOA patients. The structural abnormalities detected in the retinal mitochondria of these mutant mice indicated a disruption in mitochondrial function, which is known to play a pivotal role in ADOA pathogenesis.

Conclusions : In conclusion, this research successfully established a valuable mouse model for ADOA, which faithfully recapitulates the disease's clinical and molecular features observed in human patients. The findings from this model provide critical insights into the mechanisms underlying ADOA, particularly highlighting the role of mitochondrial dysfunction, oxidative stress, and altered energy metabolism. This model also serves as a promising platform for testing potential gene therapies and treatment strategies aimed at addressing this genetic optic neuropathy.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.