PLSCR1 promotes apoptosis and clearance of retinal ganglion cells in glaucoma pathogenesis

Glaucoma is the leading cause of irreversible blindness worldwide.In the pathogen-esis of glaucoma,activated microglia can lead to retinal ganglion cells(RGCs)apoptosis and death,however,the molecular mechanisms remain largely unknown.We demonstrate that phospholipid scramblase 1(PLSCR1)is a key regulator promoting RGCs apoptosis and their clearance by microglia.As evidenced in retinal progenitor cells and RGCs of the acute ocular hypertension(AOH)mouse model,overexpressed PLSCR1 induced its translocation from the nucleus to the cytoplasm and cytomembrane,as well as elevated phosphatidylserine exposure and reactive oxygen species generation with subsequent RGCs apoptosis and death.These damages were effectively attenuated by PLSCR1 inhibition.In the AOH model,PLSCR1 led to an increase in M1 type microglia activation and retinal neuroinflammation.Upregulation of PLSCR1 resulted in strongly elevated phagocytosis of apoptotic RGCs by activated microglia.Taken together,our study provides important insights linking activated microglia to RGCs death in the glaucoma pathogenesis and other RGC-related neurodegenerative diseases.

Current approaches to reduce or eliminate mitochondrial DNA mutations

Mitochondrial DNA （mtDNA） mutations have been impli- cated in a broad range of disorders which severely affect human health （Wallace, 1999）. Some drugs have been developed to slow down pathological changes of mitochon- drial disorders. However, there is no effective treatment for patients with mtDNA mutations, mtDNA is less protected and has fewer repair mechanisms than nuclear DNA （nDNA）. Such a reality results in a much higher mutation rate in mtDNA than that in nDNA. The mixture of mutated mtDNA versus wild-type mtDNA is known as hetero- plasmy. Mitochondrial threshold effect refers to the fact that mtDNA mutation must accumulate to high proportions （60%-90%） before respiratory activity is affected （Schon et al., 2012）. It is feasible to selectively reduce the levels of mu- tated mtDNA while sparing wild-type mtDNA to skew this ratio back to a healthier range. Here, we describe the link between mtDNA mutation and mitochondrial diseases, and we summarize several newly developed approaches with regard to the reduction or elimination of mtDNA mutation in mammals. These methods include nuclear gene modula- tion, molecular approaches targeting mutated mtDNA, mtDNA replacement, and induced pluripotent stem cell （iPSC） modeling. These various methods have their own advantages and limitations.