GSK3ss-Dependent Dysregulation of Neurodevelopment in SPG11-Patient Induced Pluripotent Stem Cell Model

Mishra HK, Prots I, Havlicek S, Kohl Z, Pérez-Brangulí F, Börstler T, Anneser L, Minakaki G, Wend H, Hampl M, Leone M, Brückner M, Klucken J, Reis A, Boyer L, Schuierer G, Behrens J, Lampert A, Engel F, Gage FH, Winkler J, Winner B (2016)

Publication Status: Published

Publication Type: Journal article

Publication year: 2016

Journal

Annals of Neurology Wiley-Blackwell

Publisher: WILEY

Book Volume: 79

Pages Range: 826-840

Journal Issue: 5

DOI: 10.1002/ana.24633

Abstract

Objective: Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC)-derived cortical neural progenitor cells (NPCs).Methods: We generated and characterized iPSC-derived NPCs and neurons from 3 SPG11 patients and 2 age-matched controls.Results: Gene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell-cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ss-signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation.Interpretation: This iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ss as a potential novel target to reverse the disease phenotype.

Authors with CRIS profile

Himanshu Kumar Mishra Department of Molecular Neurology Iryna Prots Professur für Stammzell-Modelle seltener neuraler Erkrankungen Steven Havlicek Department of Molecular Neurology Zacharias Kohl Department of Molecular Neurology Tom Börstler Professur für Stammzell-Modelle seltener neuraler Erkrankungen Georgia Minakaki Professur für Molekulare Neurologie Martin Hampl Lehrstuhl für Physiologie Martina Brückner Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Jochen Klucken Department of Molecular Neurology André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Jürgen Behrens Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Angelika Lampert Lehrstuhl für Physiologie Felix Engel Professur für Experimentelle Nieren- und Kreislaufforschung Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Salk Institute for Biological Studies US United States (USA) (US) Universität Regensburg DE Germany (DE)

How to cite

APA:

Mishra, H.K., Prots, I., Havlicek, S., Kohl, Z., Pérez-Brangulí, F., Börstler, T.,... Winner, B. (2016). GSK3ss-Dependent Dysregulation of Neurodevelopment in SPG11-Patient Induced Pluripotent Stem Cell Model. Annals of Neurology, 79(5), 826-840. https://doi.org/10.1002/ana.24633

MLA:

Mishra, Himanshu Kumar, et al. "GSK3ss-Dependent Dysregulation of Neurodevelopment in SPG11-Patient Induced Pluripotent Stem Cell Model." Annals of Neurology 79.5 (2016): 826-840.

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