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03.07.18 Identifying and targeting a nuclear transport pathway affected in premature and healthy ageing

last modified Jul 05, 2018 06:33 PM
The Jackson and Kouzarides labs present a model for how NAT10 inhibition rescues cells with phenotypes of the premature ageing disease Hutchinson-Gilford progeria syndrome
03.07.18 Identifying and targeting a nuclear transport pathway affected in premature and healthy ageing

Extract fron Fig. 8: Model for how NAT10 inhibiton rescues HGPS phenotypes

Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway

Larrieu D et al. (2018)  Sci. Signal. Vol 11, Issue 537, eaar5401. DOI: 10.1126/scisignal.aar5401

 

Abstract from the paper

Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature aging disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleocytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus.

We report that microtubule stabilization in HGPS cells sequestered the nonclassical nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localization of its cargo, including the nuclear pore protein NUP153. Consequently, nuclear Ran, nuclear anchorage of the nucleoporin TPR, and chromatin organization were disrupted, deregulating gene expression and inducing senescence. Inhibiting N-acetyltransferase 10 (NAT10) ameliorated HGPS phenotypes by rebalancing the nuclear to cytoplasmic ratio of TNPO1. This restored nuclear pore complex integrity and nuclear Ran localization, thereby correcting HGPS cellular phenotypes. We observed a similar mechanism in cells from healthy aged individuals.

This study identifies a nuclear import pathway affected in aging and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS and perhaps also for pathologies associated with normal aging.

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There is a also Focus article in the same journal that discusses this paper.

 

  • Read more about research in the Jackson lab.
  • Watch Steve Jackson describe his research on the DNA-damage response in this short video.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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