Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Abstract

Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna LCO/LCO ), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna LCO/LCO mice were entirely healthy, and Lmna LCO/LCO cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna LCO allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24 -/-mice. Moreover, treating Zmpste24 -/-cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.

Mouse models of the laminopathies

“…In Lmna LCO/LCO cells, all of the transcription of Lmna is diverted to the production of lamin C. Western blots of Lmna LCO/LCO fibroblasts with a lamin A/C antibody revealed lamin C and absolutely no lamin A, prelamin A, or progerin. The amount of lamin C protein in Lmna LCO/LCO and Lmna LCO/+ fibroblasts was higher than in wild-type cells [58].…”

“…However, Lmna LCO/− mice appeared entirely normal, and their growth rate, grip strength, and bones were indistinguishable from wild-type and Lmna LCO/LCO mice. Nuclei from Lmna LCO/LCO cells showed only a slight increase in abnormal morphology, compared to normal nuclei [58]. Also emerin targeting to the nuclear envelope was entirely normal in Lmna LCO/LCO cells, despite earlier reports that had suggested that lamin A may play a key role in directing emerin to the nuclear envelope [41,59].…”

“…Lamin C-Only Mice-Lamin C-only mice (Lmna LCO )-mice that synthesize exclusively lamin C but no prelamin A or lamin A-have also been established [58]. Normally, lamin A and lamin C transcripts are present in similar amounts in wild-type fibroblasts, as judged by northern blot analysis.…”

Accelerated ageing: from mechanism to therapy through animal models

“…Thus, the so-called ''lamin C only'' mice, carrying a Lmna allele which fails to undergo the lamin A-specific splicing, have revealed that lamin A is dispensable in mice (Fong et al 2006b). These studies have also provided additional evidence of the causative role of prelamin A accumulation in the progeroid phenotype of Zmpste24-deficient animals, thereby supporting the conclusions raised by using Lmna ?/-animals .…”

“…Using transcriptional profiling on tissues from this knockout model, we found that hyperactivation of p53 signalling plays a key role in the accelerated ageing phenotype, which is partially reversed by p53 deficiency . Moreover, the use of genetic approaches revealed that lowering the prelamin A levels results in a total rescue of this mouse model from the accelerated ageing condition Fong et al 2004;2006b). Based on this information, we have performed preclinical studies to test anti-progeria pharmacological approaches aimed to prevent the accumulation of prenylated prelamin A isoforms ).…”