Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

• DOI: 10.1111/acel.13002
• Publication Date: 2019-07-15T11:43:44Z
• Authors: Ian García‐Aguirre; Alma Alamillo‐Ini...; Ruth Rodríguez‐Pérez; Griselda Vélez‐Ag...; Elianeth Amaro‐En...; Elizabeth Jiménez...; Alejandra Vásquez...; Marco Samuel Lare...; Sara L. Morales‐L...; Reynaldo Tiburcio...; Arturo Ortega; Jonathan J Magaña; Steve J. Winder; Bulmaro Cisneros
• Keywords: Progeria; Premature aging; LMNA; Nuclear export signal; Senescence; Nuclear lamina

Abstract The study of Hutchinson–Gilford progeria syndrome (HGPS) has provided important clues to decipher mechanisms underlying aging. Progerin, a mutant lamin A, disrupts nuclear envelope structure/function, with further impairment multiple processes that culminate in senescence. Here, we demonstrate the protein export pathway is exacerbated HGPS, due progerin‐driven overexpression CRM1, thereby disturbing nucleocytoplasmic partitioning CRM1‐target proteins. Enhanced central since pharmacological inhibition CRM1 alleviates all aging hallmarks analyzed, including senescent cellular morphology, B1 downregulation, loss heterochromatin, morphology defects, and expanded nucleoli. Exogenous on other hand recapitulates HGPS phenotype normal fibroblasts. levels/activity increases age fibroblasts from healthy donors, indicating altered common hallmark pathological physiological Collectively, our findings provide novel insights into pathophysiology, identifying as potential therapeutic target HGPS.