ArticleTranslational psychiatry2018
Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression.
Article in Translational psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 27 citations in OpenAlex.
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- APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons.Molecular psychiatry · 2022Article
- Integrated Multi-Omics Analysis Reveals the Effect of Maternal Gestational Diabetes on Fetal Mouse Hippocampi.Frontiers in cell and developmental biology · 2022Article
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- NeuriteNet: A convolutional neural network for assessing morphological parameters of neurite growth.Journal of neuroscience methods · 2021Article
- The plasma peptides of Alzheimer's disease.Clinical proteomics · 2021Article
- Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder.Schizophrenia bulletin open · 2021Article
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- LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to HeterozygousFrontiers in neuroscience · 2020Article
- Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies.Brain communications · 2020Article
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Authors and funding
9 authors at 3 institutions in 1 country.
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Abstract
The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.
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