Novel Drug Candidates Improve Ganglioside Accumulation and Neural Dysfunction in GM1 Gangliosidosis Models with Autophagy Activation.
GM1 gangliosidosis
drug development
induced pluripotent stem cells
lysosomal storage disease
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
12 05 2020
12 05 2020
Historique:
received:
06
11
2019
revised:
13
03
2020
accepted:
17
03
2020
pubmed:
18
4
2020
medline:
17
4
2021
entrez:
18
4
2020
Statut:
ppublish
Résumé
GM1 gangliosidosis is a lysosomal storage disease caused by loss of lysosomal β-galactosidase activity and characterized by progressive neurodegeneration due to massive accumulation of GM1 ganglioside in the brain. Here, we generated induced pluripotent stem cells (iPSCs) derived from patients with GM1 gangliosidosis, and the resultant neurons showed impaired neurotransmitter release as a presynaptic function and accumulation of GM1 ganglioside. Treatment of normal neurons with GM1 ganglioside also disturbed presynaptic function. A high-content drug-screening system was then established and identified two compounds as drug candidates for GM1 gangliosidosis. Treatment of the patient-derived neurons with the candidate agents activated autophagy pathways, reducing GM1 ganglioside accumulation in vitro and in vivo, and restoring the presynaptic dysfunction. Our findings thus demonstrated the potential value of patient-derived iPSC lines as cellular models of GM1 gangliosidosis and revealed two potential therapeutic agents for future clinical application.
Identifiants
pubmed: 32302553
pii: S2213-6711(20)30102-8
doi: 10.1016/j.stemcr.2020.03.012
pmc: PMC7220856
pii:
doi:
Substances chimiques
Neuroprotective Agents
0
G(M1) Ganglioside
37758-47-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
909-923Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Hum Mol Genet. 2015 Dec 1;24(23):6675-86
pubmed: 26362253
Glycoconj J. 1997 Sep;14(6):729-36
pubmed: 9337086
J Hum Genet. 2009 Sep;54(9):510-5
pubmed: 19644515
Mol Genet Metab. 2008 Jun;94(2):204-11
pubmed: 18387328
J Inherit Metab Dis. 2005;28(5):797-8
pubmed: 16151914
Mol Genet Metab. 2008 Aug;94(4):391-6
pubmed: 18524657
Neuroscience. 1997 Jul;79(2):329-40
pubmed: 9200718
Autophagy. 2013 Dec;9(12):2087-102
pubmed: 24113242
Biochem Biophys Res Commun. 2008 Mar 14;367(3):616-22
pubmed: 18190792
Biochem J. 2002 Aug 15;366(Pt 1):1-13
pubmed: 12047220
Nat Methods. 2011 May;8(5):409-12
pubmed: 21460823
Mol Cell. 2016 Nov 17;64(4):835-849
pubmed: 27818143
Mol Cell. 2004 Sep 10;15(5):753-66
pubmed: 15350219
Cell Mol Life Sci. 2003 May;60(5):942-60
pubmed: 12827282
PLoS One. 2010 Oct 18;5(10):e13468
pubmed: 20976108
Acta Neuropathol. 1987;73(4):357-60
pubmed: 3113167
Cell Mol Life Sci. 2014 Jun;71(11):2017-32
pubmed: 24337808
J Pathol. 2015 Sep;237(1):98-110
pubmed: 25925601
Autophagy. 2012 May 1;8(5):719-30
pubmed: 22647656
J Neurosci. 2016 Jul 27;36(30):7911-24
pubmed: 27466336
Biochim Biophys Acta. 2009 Sep;1793(9):1496-507
pubmed: 19339210
J Neurosci. 2013 Jun 19;33(25):10195-208
pubmed: 23785136
Cell. 2007 Dec 14;131(6):1149-63
pubmed: 18083104
Stem Cells. 2015 Apr;33(4):1075-88
pubmed: 25522247
Curr Opin Pharmacol. 2009 Oct;9(5):580-8
pubmed: 19775937
Mol Genet Metab. 2012 Sep;107(1-2):173-85
pubmed: 22898113
J Neurol Sci. 1990 Jun;97(1):53-65
pubmed: 2115076
Mol Cell. 2009 Nov 13;36(3):500-11
pubmed: 19917257
Mol Genet Metab Rep. 2019 Sep 11;21:100513
pubmed: 31534909
Stem Cell Reports. 2014 May 15;2(6):866-80
pubmed: 24936472
Philos Trans R Soc Lond B Biol Sci. 1999 Feb 28;354(1381):269-79
pubmed: 10212475
Hum Mol Genet. 1997 Feb;6(2):205-11
pubmed: 9063740
Mol Genet Metab. 2012 May;106(1):92-8
pubmed: 22436580
Cell. 2007 Nov 30;131(5):861-72
pubmed: 18035408
Autophagy. 2011 Aug;7(8):883-91
pubmed: 21460612
J Med Genet. 2012 Sep;49(9):591-7
pubmed: 22892202
EMBO J. 2000 Nov 1;19(21):5720-8
pubmed: 11060023
Brain Res. 1999 Sep 25;842(2):431-8
pubmed: 10526139