In progeria cells, progerin prevents autophagosomes from fusing with lysosomes and therefore accumulates itself

In progeria cells, progerin prevents autophagosomes from fusing with lysosomes and therefore accumulates itself

A study published in Aging Cell on July 29 examined fibroblasts from patients with Hutchinson-Gilford syndrome. The authors traced how progerin disrupts the final stages of cellular waste disposal: cargo reaches the autophagosome, but the autophagosome is less able to fuse with the lysosome, where proteins are broken down.

Hutchinson-Gilford syndrome is caused by a mutation in the LMNA gene. This mutation causes the cell to produce progerin, a truncated form of lamin A. Progerin remains at the nuclear envelope and alters cellular function. During autophagy, the cell packages damaged proteins and parts of organelles into an autophagosome. The autophagosome then fuses with a lysosome, an acidic compartment containing degradative enzymes.

The authors studied fibroblasts from two patients with progeria and normal human fibroblasts engineered to express progerin. Autophagosomes formed in both models, but their maturation, fusion with lysosomes, and degradation of cargo were slower. The defect involved the delivery of cargo for lysosomal degradation, not the initiation of autophagy itself.

They separately examined two proteins involved at this stage. STX17 is located on mature autophagosomes and helps them fuse with lysosomes. LAMP1 is a component of the lysosomal membrane. In progeria cells, both proteins were less abundant or incorrectly localized. Restoring STX17 improved autophagosome maturation, while restoring LAMP1 increased the number of autophagosome fusions with lysosomes.

The authors also treated the cells with selinexor, an anticancer drug that blocks the nuclear export protein XPO1. After treatment, TFEB accumulated in the nucleus and activated lysosomal genes. Lysosomal activity increased, while cellular progerin levels decreased. In this study, selinexor was used to restore the lysosomal part of the pathway.

In a 2015 experiment, sulforaphane had already helped fibroblasts clear progerin. The new study suggests that searches for similar interventions should assess autophagosome maturation, STX17, LAMP1, and autophagosome fusion with lysosomes separately.