Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

Prelamin A is a farnesylated precursor of lamin A, a nuclear lamina protein. Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion including its processing site, causes Hutchinson-Gilford progeria syndrome. Loss-of-function mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders. Some data suggest that prelamin A also accumulates with physiological aging. Zmpste24(-/-) mice die young, at similar to 20 wk. Because ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to examine effects solely due to the presence of permanently farnesylated prelamin A. These mice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to lamin A. The Lmna(L648R)(/)(L648R) mice express only prelamin and no mature protein. Notably, nearly all survive to 65 to 70 wk, with similar to 40% of male and 75% of female Lmna(L648R)(/)(L648R) mice having near-normal lifespans of 90 wk (almost 2 y). Starting at similar to 10 wk of age, Lmna(L648R)(/)(L648R) mice of both sexes have lower body masses than controls. By similar to 20 to 30 wk of age, they exhibit detectable cranial, mandibular, and dental defects similar to those observed in Zmpste24( -/-) mice and have decreased vertebral bone density compared to age- and sex-matched controls. Cultured embryonic fibroblasts from Lmna(L648R)(/)(L648R) mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyl-transferase inhibitor. These novel mice provide a model to study the effects of farnesylated prelamin A during physiological aging.

Automated summary

Prelamin A, a farnesylated precursor of lamin A, can cause progeria syndrome when accumulated as progerin. Mutations in ZMPSTE24, the processing enzyme of prelamin A, can lead to progeroid disorders. This study generated a mouse model with permanently farnesylated prelamin A and found that these mice have extended lifespan and exhibit skeletal and nuclear defects during physiological aging.