Findings may lead to new approach to treat developmental problems
associated with cell nuclear membranes
Mutations of the gene Lmna
previously thought to be directly responsible for a group of laminopathies —
serious developmental conditions including premature aging and a form of
muscular dystrophy — in fact cause them by allowing a critical protein to
accumulate. An international collaborative group of researchers1 including
Ya-Hui Chi and co-workers at the A*STAR Institute of Medical Biology have
discovered in mice that reducing levels of the protein, Sun1, resulted in
decreased severity of the diseases and longer life spans. This breakthrough
finding may eventually lead to changes of the treatment strategy for
developmental conditions.
The inner membrane of the cell
nucleus is strengthened by a meshwork of protein filaments known collectively
as the nuclear lamina. In mammals, the Lmna gene encodes two of the proteins that
form the lamina filaments. Mice with two copies of dysfunctional Lmna genes
model human Emery-Dreifuss muscular dystrophy (EDMD), and mice with genes
incorporating a mutation that deletes 40 amino acids from the Lmna gene show
features of the premature aging syndrome Hutchinson-Gilford progeria (HGPS).
All these mice have misshapen cellular nuclei, degenerative tissues and organs,
and short lives.
Recent research has shown that,
as well as keeping the membrane in shape, the nuclear lamina is involved in
activating genes, repairing DNA and organizing the nucleus. In order to
investigate these roles, the researchers generated EDMD and HGPS model mice
with genes encoding dysfunctional Sun1, a protein involved in linking the
nuclear lamina and the cytoskeleton within the cell. To their surprise, these
mice showed milder developmental defects and lived for longer.
In fact, cells from EDMD and HGPS
model mice display an excessive accumulation of Sun1. The researchers found the
same to be true of human cells taken from those afflicted by HGPS. Their
developmental problems were alleviated by lowering the level of Sun1. Further
work suggested that the accumulation of Sun1 was the result not of increased
production of the protein, but reduced degradation.
“Collectively the findings
implicate Sun1 build-up as the common event of the disorders,” says Chi. “We
suspect that clinical trials and therapies that target the protein products of
dysfunctional genes without resolving the Sun1 accumulation are ineffective or
useless against HGPS. In fact, our experimental evidence shows that reduced
metabolic turnover of Sun1 is a major cause of HGPS.”
Chi and co-workers now want to
investigate what factors interact with Sun1 for it to accumulate, and also if
there are any other proteins responsible for HGPS.
The A*STAR-affiliated researchers
contributing to this research are from the Institute of Medical Biology
References
- Chen, C-Y., Chi, Y-H., Mutalif, R. A., Starost, M.
F., Myers, T. G., et al. Accumulation of the inner nuclear envelope
protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell 149,
565–577 (2012). |article
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