Nuclear envelope dynamics in Hutchinson-Gilford progeria syndrome

点击翻译按钮获取中文摘要

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare, premature aging disorder that leads to death at an average age of 14 years, as a result of myocardial infarction or stroke. Mutations in the LMNA gene are responsible for HGPS, which belongs to the family of laminopathies. The most common mutation associated with HGPS is a de novo heterozygous single base pair substitution at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A; the truncated protein is referred to as progerin. Lamins help maintain the shape and stability of the nuclear envelope and are involved in the regulation of DNA replication and transcription. Progerin undergoes only some of the normal posttranslational modifications and remains permanently farnesylated. The toxicity of progerin has been attributed, in part, to its farnesyl moiety.During the first round of this application, we demonstrated that progerin elicits spatiotemporal deviations in mitotic processes, particularly the processes that are dependent on proper association with the nuclear envelope and nuclear pore distribution. We contributed important and crucial data to the increasing list of cellular, genomic and metabolic defects caused by progerin. Previous studies on progerin have assessed its localization and activity during interphase, our study followed progerin throughout its inevitable participation in mitosis, a phenomenon that has been remarkably ignored to date. Our approach unraveled significant and specific delays in the mitotic redistribution of several proteins (nuclear lamins, emerin, and SUN1), including the trapping of SUN1 in the ER at the last stages of mitosis and delayed recruitment of nuclear pores in the re-assembling NE in HGPS cells. These changes were accompanied by a substantial increase in chromatin lagging, which caused binucleated cells and genomic instability.Based on these observations, we hypothesized that the critical positioning of SUN1 at the nuclear envelope and its aberrant interaction with progerin are directly implicated in the generation of an abnormal nuclear membrane system in HGPS cells. This consequently leads to alterations in the nuclear shape, NPC positioning, cellular homeostasis and function that drive HGPS cells to undergo apoptosis and premature senescence. To test this hypothesis, we propose to investigate the following Specific Aims: (1) characterize progerin intracellular trafficking and nuclear envelope association; and (2) characterize progerin-SUN1 interaction and its inevitable consequences on nuclear pore distribution and nuclear integrity.