早老症(HGPS)的发病机制与治疗策略

The Pathogenic Mechanisms and Therapeutic Strategies of Hutchinson-Gilford Progeria Syndrome

早老症(Hutchinson-Gilford Progeria Syndrome,HGPS)是一种早发而严重的过早老化性疾病.它是由于编码A/C型核纤层蛋白的LMNA基因发生点突变而引起.这个突变激活了基因11号外显子上一个隐蔽的剪接位点,产生了一种被截短了50个氨基酸的A型核纤层蛋白.然而,一个广泛分布于核膜上结构蛋白的突变,如何引起HGPS患者的早老表现,目前还不太清楚.最近研究发现,HGPS患者的细胞核结构与功能发生了各种异常,主要表现在:progerin蓄积与核变形、细胞核机械性质的改变、组蛋白修饰方式与外遗传控制的改变、基因表达调控异常、p53信号传导通路激活和基因组不稳定等方面.目前存在机械应激假说和基因表达失控假说两种假说解释HGPS的发病机制.对于HGPS患者,尚无有效的临床干预措施,但有学者提出了一些治疗策略,如应用法尼基化的抑制剂、反义寡核苷酸和RNA干扰方法.HGPS被认为是研究正常衰老机制的一个模型.对HGPS深入研究将有助于阐明A型核纤层蛋白和核膜的正常生理功能,及其在生理衰老和疾病中的作用.

Hutchinson-Gilford progeria syndrome （HGPS） is an early onset severe premature aging disorder due to a point mutation in LMNA gene which encodes nuclear lamin A/C. The mutation activates a cryptic splice site within exon 11 of LMNA, resulting in a 50-amino acid in-frame deletion in prelamin A. However, it is not clear how the mutation in a structural protein under the nuclear envelope could give rise to premature aging phenotypes. Recent studies showed that various abnormalities have been found in nuclear structures and functions of HGPS cells, mainly including progerin accumulation and nuclear morphology abnormalities, altered nuclear mechanical properties, changes of histone methylation patterns and epigenetic control, gene misregulation, p53 signalling activation, and increased genomic instability. Two hypotheses recently emerged in the explanation of the pathogenic mechanisms contributing to HGPS. No effective clinical intervention has been developed so far for HGPS. Several fascinating therapeutic strategies have recently been provided, such as farnesyltransferase inhibitors, antisense oligonucleotides and RNA interference. HGPS has been considered to be a model for studying the mechanisms responsible for normal aging. This study will help to elucidate the physiological functions of lamin A and nuclear envelope, together with their roles in normal aging process and diseases.