Progerin Hinders Autophagy Flux at Its Final Stages in Hutchinson‐Gilford Progeria Syndrome Cells, Preventing Its Own Autophagic Degradation

In Hutchinson-Gilford progeria syndrome (HGPS), dysfunctional autophagy results in the accumulation of progerin, a lamin A mutant variant that alters a plethora of processes, inducing senescence and driving premature aging. Therefore, the elimination of progerin through autophagy restoration emerges as a therapeutic intervention against HGPS. However, a comprehensive study of autophagy flux in HGPS remains to be addressed. In this study, the dynamics of autophagy in HGPS fibroblasts were analyzed utilizing different HGPS cell models and experimental approaches. The autophagy-associated transcriptomic profile was determined, and the autophagy-lysosome axis was comprehensively analyzed. We demonstrated that progerin induces the formation of autophagosomes but impairs their maturation and subsequent fusion with lysosomes. This alteration is attributed in part to the progerin-mediated decreased expression of STX17, a marker of mature autophagosomes, and LAMP1, a membrane lysosomal protein, as well as the presence of defective lysosomes. In line with this, the rescue of STX17 and LAMP1 expression improved autophagy flux. Interestingly, treatment of HGPS fibroblasts with Selinexor, an autophagy activator, elicited nuclear accumulation of TFEB and enhanced lysosomal biogenesis and function, thereby activating autophagy. Selinexor treatment improved both autophagosome maturation and autophagosome-lysosome fusion, which ultimately led to effective autophagic degradation of progerin. In summary, progerin impedes proper autophagy flux, thus preventing its own autophagic degradation, which underscores the relevance of targeting the autophagy-lysosome pathway to counteract the toxic accumulation of progerin.