The Relationship Between Sex and Progression of Retinal Degenerative Disease

PROJECT SUMMARY. Neurodegenerative disorders represent major sources of human suffering, yet the factors influencing disease severity remain poorly understood. Sex has been implicated as one such factor, yet there remains a considerable gap in our understanding of how sex hormones affect neurodegenerative processes. Retinitis pigmentosa (RP) is a retinal neurodegeneration in which photoreceptors undergo a progressive and irreversible degeneration leading to blindness. We recently discovered that females have a worse outcome than males in a mouse model of RP caused by the rhodopsin P23H mutation (Rho P23H), the most common cause of autosomal dominant RP in humans. Further, we showed that this association is caused by an adverse effect of circulating female sex hormones on retinal neurons, which can be ameliorated by depletion of these female hormones. RP can be caused by a wide diversity of genetic mutations, which creates a daunting obstacle to therapeutic targeting of each individual mutation. However, many of these mutations result in similar phenotypes and converge on shared downstream pathways leading to photoreceptor neurodegeneration. The objective of this proposal is to determine the molecular mechanisms by which female sex hormones adversely impact the severity of photoreceptor neurodegeneration. To investigate how the female sex hormones play a role in this common pathway of photoreceptor neurodegeneration, we propose to expand on our work in the Rho P23H RP mouse. We hypothesize that female sex hormones interact with key cell death and cell stress pathways downstream of the genetic mutation, to worsen photoreceptor degeneration. The findings from these aims will provide novel insights into how sex hormones modulate the pathogenesis and severity of neurogenerative disease. Results from these aims will identify the precise female hormones and any interconversions of these hormones driving advanced retinal degeneration in RP, and the mechanism by which this occurs. These findings have far-reaching implications for clinical trial design, such as sex stratification, hormonal medications, consideration of pre-, peri- , and post-menopausal states, and the use of hormonal therapy in females with certain neurogenerative disorders such as RP.