Mishra, Himanshu K. and Prots, Iryna and Havlicek, Steven and Kohl, Zacharias and Perez-Branguli, Francesc and Boerstler, Tom and Anneser, Lukas and Minakaki, Georgia and Wend, Holger and Hampl, Martin and Leone, Marina and Brueckner, Martina and Klucken, Jochen and Reis, Andre and Boyer, Leah and Schuierer, Gerhard and Behrens, Juergen and Lampert, Angelika and Engel, Felix B. and Gage, Fred H. and Winkler, Juergen and Winner, Beate (2016) GSK3ss-Dependent Dysregulation of Neurodevelopment in SPG11-Patient Induced Pluripotent Stem Cell Model. ANNALS OF NEUROLOGY, 79 (5). pp. 826-840. ISSN 0364-5134, 1531-8249
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEREDITARY SPASTIC PARAPLEGIA; THIN CORPUS-CALLOSUM; CYCLE PROGRESSION; SPATACSIN; PROLIFERATION; SPG11; CYTOKINESIS; MUTATIONS; CARDIOMYOCYTES; DEFECTS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Röntgendiagnostik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2019 13:34 |
| Last Modified: | 15 Mar 2019 13:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3015 |
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