Role for prelamin A in premature and physiological aging

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PROJECT SUMMARY This project aims to define the role of farnesylated prelamin A in premature and physiological aging. Genetic mutations leading to defective processing of prelamin A, the precursor for the nuclear scaffold protein lamin A, result in persistence of its farnesyl modification and cause premature aging disorders. The best known of these is Hutchinson-Gilford progeria syndrome (HGPS), in which a truncated farnesylated prelamin A variant called “progerin” is expressed. Mandibuloacral dysplasia-type B (MAD-B) is a related disease, where unprocessed farnesylated prelamin A itself accumulates in cells. Some evidence suggests that prelamin A also accumulates during physiological aging. However, the mechanistic role of farnesylated prelamin A in premature aging disorders remains unclear, and its association with physiological aging has not been rigorously tested. We hypothesize that prelamin A is a driver of osteoporosis and cardiovascular disease that occurs in premature and possibly physiological aging. To specifically examine the consequences of prelamin A accumulation, we generated a novel mouse strain (LmnaL648R/L648R) with a mutation that abolishes its processing by the zinc metalloprotease ZMPSTE24. These mice express solely prelamin A (and no mature lamin A), exhibit profound bone loss, but have a significantly longer lifespan than other progeria models and are thus ideal to study the effects of prelamin A during aging. In Aim 1, we will determine how prelamin A affects the number, function, development, transcriptomes and signaling of bone cells, and compare these to what occurs in physiological aging. We will also assess whether these mice develop vascular disease as they age or develop accelerated atherosclerosis when combined with genetic (Ldlr-/-) and high-fat diet interventions that sensitize mice to atherosclerosis. In Aim 2, we will determine how prelamin A affects cultured cells and define the mechanism(s) by which it promotes cellular alterations related to aging. We will carry out chronological transcriptomic analyses in cultured cells to define the earliest events promoted by prelamin A to distinguish causal changes from chronic responses. We will also test the hypothesis that prelamin A induces nuclear envelope rupture that could stimulate a cytosolic DNA sensor and lead to a transcriptional program of inflammation. We will relate the mechanistic insights obtained from these in vitro experiments to affected cells in the LmnaL648R/L648R mice. In Aim 3, we will determine if prelamin A actually accumulates during physiological aging by examining bone and vascular tissue of young and old mice. We will also probe human tissue arrays and a panel of fibroblasts from young and aged individuals for prelamin A. Elucidating the cellular mechanisms and consequences of prelamin A accumulation could change clinical paradigms for the treatment of prelamin A-based premature aging disorders. More broadly, the results of this project could rigorously implicate prelamin A in physiological aging, identifying it as a potential therapeutic target for age-associated osteoporosis, cardiovascular disease, and possibly other ailments.