title: GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Himanshu K
authors.initials: HK
authors.lastname: Mishra
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Havlicek
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Francesc
authors.initials: F
authors.lastname: Perez-Branguli
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Boerstler
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Anneser
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Minakaki
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Wend
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hampl
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Leone
authors.affiliation: Department of Experimental Medicine II, Nikolaus-Fiebiger-Centre for Molecular Medicine, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Brückner
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Reis
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Boyer
authors.affiliation: Institute of Neuroradiology, Center of Neuroradiology, Regensburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuierer
authors.affiliation: Department of Experimental Medicine II, Nikolaus-Fiebiger-Centre for Molecular Medicine, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Behrens
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.|Institute of Physiology, RWTH University, Aachen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.affiliation: Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Engel
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander-Universitaet Erlangen-Nuernberg (FAU), Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner