A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds

Methods. 2016 Mar 1:96:46-58. doi: 10.1016/j.ymeth.2015.08.024. Epub 2015 Sep 1.

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is an early onset lethal premature aging disorder caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A. The presence of progerin causes extensive morphological, epigenetic and DNA damage related nuclear defects that ultimately disrupt tissue and organismal functions. Hypothesis-driven approaches focused on HGPS affected pathways have been used in attempts to identify druggable targets with anti-progeroid effects. Here, we report an unbiased discovery approach to HGPS by implementation of a high-throughput, high-content imaging based screening method that enables systematic identification of small molecules that prevent the formation of multiple progerin-induced aging defects. Screening a library of 2816 FDA approved drugs, we identified retinoids as a novel class of compounds that reverses aging defects in HGPS patient skin fibroblasts. These findings establish a novel approach to anti-progeroid drug discovery.

Keywords: FDA-approved compounds; HGPS; High-content imaging; High-throughput screening; Progerin; Retinoids.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cellular Senescence / drug effects*
  • Cellular Senescence / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Epigenesis, Genetic
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • High-Throughput Screening Assays*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lamin Type A / antagonists & inhibitors*
  • Lamin Type A / genetics
  • Lamin Type A / metabolism
  • Lamin Type B / genetics
  • Lamin Type B / metabolism
  • Molecular Imaging / methods*
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Primary Cell Culture
  • Progeria / genetics
  • Progeria / metabolism
  • Progeria / pathology
  • Retinoids / pharmacology*
  • Small Molecule Libraries / pharmacology
  • Transfection
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • CBX3 protein, human
  • Chromosomal Proteins, Non-Histone
  • H2AX protein, human
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Lamin Type A
  • Lamin Type B
  • Retinoids
  • Small Molecule Libraries
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • prelamin A