Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation

Chiang, Jason; Y, Su; Wen, Zhiping; Yoritomo, Nadine; Ca, Ross; Margolis, R E; Song, Hongjun; Ming, Guo Li

doi:10.1038/mp.2011.13

Cited by 168 publications

(136 citation statements)

References 10 publications

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“…Recently, two studies using induced pluripotent stem cell techniques showed that neurons derived from fibroblasts of human schizophrenia patients had reduced neurite numbers and neuronal connectivity (Brennand et al, 2011;Chiang et al, 2011). In our study, knockdown of ULK4 greatly decreased neuritogenesis.…”

Section: Discussionmentioning

confidence: 54%

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Luo

Hunter

et al. 2013

Journal of Cell Science

121

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Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (P50.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.

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Section: Discussionmentioning

confidence: 54%

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Luo

Hunter

et al. 2013

Journal of Cell Science

121

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“…To avoid the persistent expression of reprogramming transgenes that may interfere with pathological analyses during differentiation [18][19][20][21], our study employed nonintegrating episomal vectors [12,[22][23][24]. We demonstrate that these FAD patientderived hiPSCs expressed the original pathogenic mutation and can be consistently differentiated into phenotypically and physiologically mature neurons with amyloidogenic properties.…”

mentioning

confidence: 99%

“…Despite earlier predictions that these breakthroughs would be relevant only to developmental disorders, there has been a recent swell of articles on the use of hiPSCs for modeling neurodegenerative diseases [11][12][13][14]. Such models have now become available for AD using fibroblasts from patients with familial AD (FAD) and sporadic AD [15][16][17].…”

mentioning

confidence: 99%

Induced Pluripotent Stem Cells from Familial Alzheimer's Disease Patients Differentiate into Mature Neurons with Amyloidogenic Properties

Mahairaki

Ryu

Peters

et al. 2014

Stem Cells and Development

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Although the majority of Alzheimer's disease (AD) cases are sporadic, about 5% of cases are inherited in an autosomal dominant pattern as familial AD (FAD) and manifest at an early age. Mutations in the presenilin 1 (PSEN1) gene account for the majority of early-onset FAD. Here, we describe the generation of virus-free human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of patients harboring the FAD PSEN1 mutation A246E and fibroblasts from healthy age-matched controls using nonintegrating episomal vectors. We have differentiated these hiPSC lines to the neuronal lineage and demonstrated that hiPSC-derived neurons have mature phenotypic and physiological properties. Neurons from mutant hiPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in b-amyloid (Ab)42/Ab40 ratio. FAD hiPSCs harboring disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis.

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“…Using induced pluripotent stem cells it is shown that neurons derived from schizophrenic fibroblasts have decreased neurite numbers and reduced neuronal connectivity. 34,35 ULK4 lesions also compromise neurotigenesis in the mouse brain and in human neuroblastoma cells. 5 However, it remains to be seen if ULK4 deletion/ mutation affects neuronal differentiation in human pluripotent stem cells.…”

mentioning

confidence: 99%

Multiple roles of Ulk4 in neurogenesis and brain function

Liu

O’Brien

et al. 2017

Neurogenesis

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Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation

Cited by 168 publications

References 10 publications

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

Induced Pluripotent Stem Cells from Familial Alzheimer's Disease Patients Differentiate into Mature Neurons with Amyloidogenic Properties

Multiple roles of Ulk4 in neurogenesis and brain function

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