The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B.-猫眼课题宝

DOI：

10.1080/19491034.2023.2288476

发表时间：

2023-12

期刊：

Nucleus (Austin, Tex.)

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10730222/

几种相关的早衰症是由前核纤层蛋白 A 的翻译后加工缺陷引起的，前核纤层蛋白 A 是核支架蛋白核纤层蛋白 A 的前体，由 LMNA 编码。 Prelamin A 在其 C 末端经历法尼基化和其他修饰。随后，法呢基化的 C 末端片段被锌金属蛋白酶 ZMPSTE24 裂解。早衰症哈钦森·吉尔福德早衰综合症 (HGPS) 和相关的早衰性疾病下颌骨发育不良 (MAD-B) 分别是由 LMNA 和 ZMPSTE24 突变引起的，这些突变导致无法处理核纤层蛋白 A 前体并永久积累法尼基化形式的前核纤层蛋白 A。法尼基转移酶抑制剂 (FTI) lonafarnib 已知可以纠正 HGPS 患者细胞的异常核形态，延长 HGPS 儿童的寿命。重要的是，与之前的报告相反，我们在此表明，FTI 治疗还可以改善 ZMPSTE24（P248L 或 L425P）突变的 MAD-B 患者细胞中的异常核表型。正如预期的那样，lonafarnib 不会纠正具有核纤层蛋白 A 加工能力突变的细胞的核缺陷。我们还检查了两个具有普遍核纤层病突变 LMNA-R644C 的个体的成纤维细胞中前核纤层蛋白 A 的加工。尽管残基 R644 靠近前核纤层蛋白 A 裂解位点，但 R644C 患者细胞系均未显示前核纤层蛋白 A 加工缺陷，并且均具有正常的核形态。这项工作阐明了前核纤层蛋白 A 的加工状态和 FTI 在多种核纤层蛋白病患者细胞中的作用，并支持 FDA 批准 FTI Zokinvy 用于加工缺陷型早衰样核纤层蛋白病患者的适应症，但不适用于加工熟练的核纤层蛋白病患者。

Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by LMNA. Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24, respectively, that result in failure to process the lamin A precursor and accumulate permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS patient cells and improves lifespan in children with HGPS. Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for cells with lamin A processing-proficient mutations. We also examine prelamin A processing in fibroblasts from two individuals with a prevalent laminopathy mutation LMNA-R644C. Despite the proximity of residue R644 to the prelamin A cleavage site, neither R644C patient cell line shows a prelamin A processing defect, and both have normal nuclear morphology. This work clarifies the prelamin A processing status and role of FTIs in a variety of laminopathy patient cells and supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies.