A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds.
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.
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nard
N
Kubben
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Kyle R
KR
Brimacombe
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Megan
M
Donegan
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Zhuyin
Z
Li
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.
Tom
T
Misteli
D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D034904:Lamin Type A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D057054:Molecular Imaging / Q000379:methods*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D061251:Primary Cell Culture; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012176:Retinoids / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1
C518294:CBX3 protein, human; D002868:Chromosomal Proteins, Non-Histone; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D034921:Lamin Type B; D012176:Retinoids; D054852:Small Molecule Libraries; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C090764:prelamin A
FDA-approved compounds; HGPS; High-content imaging; High-throughput screening; Progerin; Retinoids