Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice.
Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice.
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DOI：
10.1073/pnas.2118695119
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发表时间：
2022-03-01
影响因子：
11.1
通讯作者：
Worman HJ
中科院分区：
文献类型：
--
作者：
Wang Y;Shilagardi K;Hsu T;Odinammadu KO;Maruyama T;Wu W;Lin CS;Damoci CB;Spear ED;Shin JY;Hsu W;Michaelis S;Worman HJ
锌金属蛋白酶ZMPSTE 24去除前核纤层蛋白A的最后15个氨基酸，包括法尼基化半胱氨酸，以产生成熟核纤层蛋白A。过早老化病症Hutchinson-Gilford早衰综合征是由永久法尼基化的前核纤层蛋白A变体缺乏ZMPSTE 24切割位点引起的。ZMPSTE 24功能丧失导致法尼基化前层蛋白A的积累并导致早老性疾病。一些研究表明前层蛋白A参与了生理衰老。我们描述了在前层蛋白A中具有氨基酸取代的小鼠，其阻断ZMPSTE 24催化的裂解。这些小鼠发展出早老样表型，但与那些模拟Hutchinson-Gilford早衰综合征或ZMPSTE 24缺陷的小鼠相比，这些小鼠具有接近正常的寿命，从而提供了一个模型来研究法尼基化的前核纤层蛋白A在衰老过程中的作用。前体蛋白A是核纤层蛋白A的法尼基化前体。具有包括其加工位点在内的内部缺失的法尼基化的前核层蛋白A变体早老蛋白的积累导致Hutchinson-Gilford早老综合征。ZMPSTE 24（编码前核层蛋白A加工酶）的功能缺失突变导致全长法尼基化前核层蛋白A的积累，并引起相关的早衰症。一些数据表明，前层蛋白A也积累与生理老化。Zmpste 24 −/−小鼠在20周时夭折。由于ZMPSTE 24具有除了前层蛋白A加工之外的功能，我们产生了小鼠模型来检查仅由于永久法尼基化的前层蛋白A的存在而产生的作用。这些小鼠在前核纤层蛋白A中具有L 648 R氨基酸取代，其阻断ZMPSTE 24催化加工成核纤层蛋白A。LmnaL 648 R/L 648 R小鼠仅表达前层蛋白而不表达成熟蛋白。值得注意的是，几乎所有小鼠都存活到65至70周，其中约40%的雄性和75%的雌性LmnaL 648 R/L 648 R小鼠具有接近正常的90周（几乎2年）寿命。从10周龄开始，两种性别的LmnaL 648 R/L 648 R小鼠的体重均低于对照组。在20 - 30周龄时，它们表现出与Zmpste 24 −/−小鼠相似的可检测到的颅骨、下颌骨和牙齿缺陷，并且与年龄和性别匹配的对照组相比，椎骨骨密度降低。来自LmnaL 648 R/L 648 R小鼠的培养胚胎成纤维细胞具有异常的核形态，其通过用蛋白法尼基转移酶抑制剂处理是可逆的。这些新的小鼠提供了一个模型，以研究法尼基化的前层蛋白A在生理衰老过程中的作用。
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. 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 ∼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 LmnaL648R/L648R mice express only prelamin and no mature protein. Notably, nearly all survive to 65 to 70 wk, with ∼40% of male and 75% of female LmnaL648R/L648R mice having near-normal lifespans of 90 wk (almost 2 y). Starting at ∼10 wk of age, LmnaL648R/L648R mice of both sexes have lower body masses than controls. By ∼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 LmnaL648R/L648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyltransferase inhibitor. These novel mice provide a model to study the effects of farnesylated prelamin A during physiological aging.
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DOI：
10.1073/pnas.1906713117
发表时间：
2020-06-02
影响因子：
11.1
作者：
Cubria, Maria B.;Suarez, Sebastian;Nazarian, Ara
通讯作者：
Nazarian, Ara
DOI：
10.1073/pnas.192460799
发表时间：
2002-10-01
影响因子：
11.1
作者：
Bergo, MO;Gavino, B;Young, SG
通讯作者：
Young, SG
影响因子：
7.8
作者：
Cabral WA;Tavarez UL;Beeram I;Yeritsyan D;Boku YD;Eckhaus MA;Nazarian A;Erdos MR;Collins FS
通讯作者：
Collins FS
影响因子：
37.8
作者：
Hamczyk MR;Villa-Bellosta R;Gonzalo P;Andrés-Manzano MJ;Nogales P;Bentzon JF;López-Otín C;Andrés V
通讯作者：
Andrés V
影响因子：
56.9
作者：
Fong, LG;Frost, D;Young, SG
通讯作者：
Young, SG