Open AccessAbolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice
Author(s) -
Yuexia Wang,
Khurts Shilagardi,
Trunee Hsu,
Kamsi O. Odinammadu,
Takamitsu Maruyama,
Wei Wu,
ChyuanSheng Lin,
Christopher B. Damoci,
Eric D. Spear,
Jung-Youn Shin,
Wei-Hsuan Hsu,
Susan Michaelis,
Howard J. Worman
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2118695119
Subject(s) - progeria , lamin , phenotype , biology , premature aging , cleavage (geology) , werner syndrome , genetics , biochemistry , gene , helicase , paleontology , rna , fracture (geology)
Significance The zinc metalloprotease ZMPSTE24 removes the last 15 amino acids of prelamin A, including a farnesylated cysteine, to produce mature lamin A. The premature aging disorder Hutchinson–Gilford progeria syndrome is caused by a permanently farnesylated prelamin A variant lacking the ZMPSTE24 cleavage site. ZMPSTE24 loss of function leads to the accumulation of farnesylated prelamin A and causes progeroid disorders. Some studies have implicated prelamin A in physiological aging. We describe mice with an amino acid substitution in prelamin A that blocks the ZMPSTE24-catalyzed cleavage. These mice develop progeroid phenotypes but, in contrast to those modeling Hutchinson–Gilford progeria syndrome or ZMPSTE24 deficiency, have near-normal lifespans, thus providing a model to study the effects of farnesylated prelamin A during aging.