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Ann Neurol. 2016 May;79(5):826-840. doi: 10.1002/ana.24633.

GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.

Author information

1
IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
2
Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
3
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
4
Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
5
Department of Experimental Medicine II, Nikolaus-Fiebiger-Centre for Molecular Medicine, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
6
Institute of Human Genetics, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
7
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
8
Institute of Neuroradiology, Center of Neuroradiology, Regensburg, Germany.
9
Institute of Physiology, RWTH University, Aachen, Germany.

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. Ann Neurol 2016;79:826-840.

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