Progranulin Insufficiency Affects Lysosomal Homeostasis in Retinal Pigment Epithelium

Abstract

Background: Homozygous loss-of-function progranulin gene (GRN) mutation carriers develop adultonset neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Clinically, NCL patients display retinal degeneration and visual dysfunction. However, there is little information about the effects of progranulin dysfunction on lysosomal function of the retinal pigment epithelium (RPE). Materials and Methods: We performed RNA interference knock down of progranulin in primary human RPE (hRPE) cells and observed RPE function and lysosomal activity. Results: Progranulin localized to the lysosome in RPE cells. Loss of progranulin did not affect the biogenesis of lysosomes in RPE cells, while it was necessary for the activation of lysosomal proteases. Furthermore, progranulin deficiency decreased cell viability and disrupted the cell-cell junctions. Conclusion: Our results demonstrate that progranulin insufficiency disturbs lysosomal activity and physiological functions in RPE cells.

Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43

“…A progranulin (PGRN) haploinsufficiency because of a loss-of-function mutation in the PGRN gene causes FTLD-TDP ( 32 , 33 ). Although the function of PGRN remains debatable ( 34 ), evidence suggests that it controls lysosomal functions ( 35 , 36 , 37 , 38 , 39 ) and autophagy ( 29 , 36 , 40 , 41 , 42 ). High numbers of EV were detected in PGRN-deficient mice and FTLD-TDP patients with a PGRN gene mutation ( 43 ).…”