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

Methods : a Companion to Methods in Enzymology
Nard KubbenTom Misteli

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.

References

Oct 17, 2002·Analytical Biochemistry·Emma Rennel, Pär Gerwins
Oct 21, 2004·The Journal of Pathology·Jos L V BroersFrans C S Ramaekers
Sep 1, 2005·Proceedings of the National Academy of Sciences of the United States of America·Julia I TothLoren G Fong
Mar 3, 2006·The Journal of Clinical Investigation·Loren G FongStephen G Young
Apr 29, 2006·Science·Paola Scaffidi, Tom Misteli
Apr 24, 2007·Nature Reviews. Molecular Cell Biology·Brian A KudlowRaymond J Monnat
Sep 13, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yiyong LiuYue Zou
Oct 11, 2007·Drugs of Today·Ishido Miwako, Hiroyuki Kagechika
Mar 4, 2008·Nature Cell Biology·Paola Scaffidi, Tom Misteli
Sep 8, 2009·Nature Cell Biology·Gianluca PegoraroTom Misteli
Apr 14, 2010·BMC Bioinformatics·Oliver PelzMichael Boutros
Jul 24, 2010·Nature Reviews. Molecular Cell Biology·Christopher R Burtner, Brian K Kennedy
Apr 21, 2011·Molecular Cell·Laia Bosch-PreseguéAlejandro Vaquero
May 31, 2011·Frontiers in Bioscience (Scholar Edition)·Jose M GonzalezVicente Andres
Sep 23, 2011·Molecular & Cellular Proteomics : MCP·François-Michel BoisvertAngus I Lamond
May 23, 2012·Chromosoma·Nard KubbenTom Misteli
Sep 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Leslie B GordonMark W Kieran
Nov 28, 2012·Tetrahedron Letters·Bhaskar C DasTodd Evans
Feb 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Chloe M FunkhouserMonica Olvera de la Cruz
Mar 19, 2013·Aging Cell·Miron ProkocimerYosef Gruenbaum
Aug 10, 2013·Science·Vassilis RoukosTom Misteli
Feb 4, 2014·Cell·Leslie B GordonTom Misteli
Mar 14, 2014·Molecular Biology of the Cell·Travis A DittmerTom Misteli
Mar 19, 2014·EMBO Reports·Isabel C Lopez-MejiaJamal Tazi
May 3, 2014·Science·Delphine LarrieuStephen P Jackson

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Citations

Feb 9, 2016·Neuroscience·S KálmánK Mirnics
Feb 6, 2016·Histochemistry and Cell Biology·Sandra Vidak, Roland Foisner
Jul 5, 2016·Ageing Research Reviews·Susana GonzaloPeter Askjaer
Jan 18, 2016·Methods : a Companion to Methods in Enzymology·Gianluca Pegoraro, Tom Misteli
Jun 4, 2016·Cell·Nard KubbenTom Misteli
Apr 26, 2018·Cell Transplantation·Shoubing Zhang, Enkui Duan
Jul 4, 2019·Cells·Raquel Romero-BuenoAgnieszka Dobrzynska
Aug 31, 2019·Chemical Biology & Drug Design·Javier KlettCarmen Blanco-Aparicio
Dec 14, 2019·Proteomics·Nuria Coll-BonfillSusana Gonzalo
Aug 30, 2020·Clinical Genetics·Franziska SchnabelBernd Wollnik
Sep 1, 2017·Nature Communications·Abigail Buchwalter, Martin W Hetzer
Jul 20, 2017·Npj Aging and Mechanisms of Disease·Anne-Laure EgesipeXavier Nissan
May 10, 2016·Nucleus·Agnieszka DobrzynskaPeter Askjaer
Jul 8, 2019·GeroScience·Susana Gonzalo, Nuria Coll-Bonfill
Apr 13, 2020·Methods : a Companion to Methods in Enzymology·Solenn M GuilbertXavier Nissan
Jun 9, 2020·Ageing Research Reviews·Brenna OsborneMorten Scheibye-Knudsen

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