Project: C01

Mitochondrial DNA at the interface between mitochondrial dysfunction and neuroinflammation in glaucoma

Glaucoma is an age-associated disease characterized by progressive retinal ganglion cell (RGC) loss and degeneration of optic nerve axons and the leading cause of irreversible blindness worldwide. An estimated 57.5 million people worldwide are affected by primary open angle glaucoma (POAG) with a prevalence of 2.4%. Increased intraocular pressure (IOP) is a main risk factor for development of glaucoma and lowering IOP is the most common treatment to slow disease progression. However, about one third of patients develop normal tension glaucoma (NTG), while some people with elevated IOP never develop the disease. Also, progression of the neurodegeneration is observed even in patients with pharmacologically controlled IOP.

Despite the lack of understanding of the exact mechanism that initiates the pathogenesis of glaucoma, mitochondrial dysfunction is believed to be responsible for the development and progression of glaucoma. In agreement, increased levels of mtDNA mutations are found to be associated with RGC death in both glaucoma patients and an experimental glaucoma model. While respiratory chain deficiency was considered to be the main causal link to most pathologies arising from mitochondrial dysfunction, the discovery of mitochondrial damage-associated molecular patterns (mtDAMPs) adds another layer to the complexity of putative involvement of mitochondrial dysfunction in glaucoma, in particular in the immune cell activation and subsequent neuroinflammation.

Although it is well known that glaucomatous damage is associated with mitochondrial dysfunction linked to higher levels of mtDNA mutations and neuroinflammation, the causative link between the accumulation of mtDNA mutations and neuroinflammation in glaucoma has not been studied. In this project, the candidate will investigate the hypothesis is that neuroinflammation is central in glaucoma, and that increased mtDNA damage causes inflammation by activating microglia in retina rendering RGCs vulnerable to external stimuli.

Key methods: in vivo transgenic and induced glaucoma models, IF, mtDNA sequencing, mitochondrial characterization techniques, proteomics, scRNA-seq, protein and RNA analysis