As one ages, the physiology and structure of the retina begins to degrade, increasing the susceptibility to retinal diseases including glaucoma and macular degeneration.

This is a process that plays out over months or years, whereby neurons gradually die leading to dysfunction, vision loss, and severe reduction in quality of life. As the population is ageing worldwide, the identification of molecular pathways regulating cell-specific degenerations are crucial for developing new therapies to slow, or reverse, age-related decline. Despite a significant appreciation for the consequences of ageing on retinal health, we do not yet understand the precise cellular and molecular dysfunctions leading to degeneration with advancing age.

Animal models are widely used in ageing studies, however ethical considerations, long lifespans (> two years) and associated costs limit their feasibility. To overcome this limitation, we will establish the African turquoise killifish (Nothobranchius furzeri), a freshwater teleost with conserved retinal structure and comparatively short lifespan (4-6 months), as a new model for retinal aging. The killifish has a sequenced genome, is genetically tractable, and presents retinal degenerations akin to the aged human retina. We use immunohistochemistry, scRNA-seq, mRNA labelling and transgenesis to uncover cellular and molecular mechanisms resulting in glial and neuronal degenerations in the context of ageing. See below for more information on the specific projects carried out by each member of the team.

People working on this

Relevant literature

Bergmans S§, Noel NCL§, Masin L, Harding E, Krzywanska AM, Rajagopal A, Hu CK, Arckens L, Ruzycki PA*, MacDonald RB*, Clark BS*, Moons L*. 2024. Age-related dysregulation of the retinal transcriptome in the African turquoise killifish. Submitted. *Co-corresponding authors. bioRxiv: http://biorxiv.org/content/early/2024/02/23/2024.02.21.581372

Kothurkar A§, Patient GS§, Noel NCL, Chu CJ*, MacDonald RB*. Iterative Bleaching Extends Multiplexity (IBEX) Imaging facilitates simultaneous identification of all cell types in the vertebrate retina. *Corresponding author. bioRxiv: https://www.biorxiv.org/content/10.1101/2024.02.28.582563v1?ct=

Martins RR, Zamzam M, Moosajee M, Thummel R, Henriques CM*, MacDonald RB*. 2022. Müller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina. Ageing Cell. 21:e13597. *Co- corresponding author. https://doi.org/10.1111/acel.13597 

Keatinge M*, Gegg ME.*, Watson L, Mortiboys H, Bui H, Lefeber DJ, van Rens A, MacDonald RB*, Bandmann O*. 2023. Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency. Disease models and mechanisms. *Co- corresponding author. https://doi.org/10.1101/702340