Cutting edge Seminar

 

Speaker:  Hideyuki Okano （Professor, Department of Physiology, Graduate School of Medicine, Keio University）

Title:  Modeling of Human Neurological/Psychiatric Disorders using iPS cells and Transgenic Non-Human Primates.

 

 

Date&Time: 10 Apr. (Wed.) 2019, 12:00- 13:00

Venue: Conference Room(1F), IMEG

 

Abstract:

What makes the investigation of human psychiatric/psychiatric disorders so difficult? This could be attributed to the following reasons 1) Diseases model mice do not always recapitulate the pathophysiology of human diseases, 2) It is extremely difficult to investigate what is taking place in vivo at the onset of the disease due to the low accessibility to the pathological foci in the brain, and 3) The responsible neuronal circuits for the phenotype are not identified. In order to overcome these difficulties, we took advantage of iPS cell technologies and transgenic non-human primates for modeling human psychiatric/psychiatric disorders.

So far, we have established iPS cells from the patients of about 40 human psychiatric/psychiatric disorders and characterized their pathophysiology, including Alzheimer disease (Yagi et al., Human Mol Genet, 2011; Imaizumi et al., Stem Cell Reports, 2016), Parkinson disease (Imaizumi et al., Mol Brain, 2012; Ohta et al., Human Mol Genet, 2015; Matsumoto et al., Stem Cell Reports, 2016), ALS (Imaizumi et al., Stem Cell Reports; Ichiyanagi et al., Stem Cell Reports, 2016; Fujimori et al. Nat Med, 2018), Rett syndrome (Andoh-Noda et al., Mol Brain, 2015) and Pelizaues-Merzbacher disease (Kuroiwa-Numasawa et all., Stem Cell Reports, 2014). Using iPSC-technology to generate stem and differentiated cells retaining the patients’ full genetic information, we have established a large number of in vitro cellular models of sporadic ALS (ALS). These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.

Furthermore, for faithfully modeling the human psychiatric/psychiatric disorders in vivo, we developed transgenic non-human primates (common marmosets) with germline transmission (Sasaki et al., Nature, 20092015; Sato et al., Cell Stem Cell, 2016). In the present talk, we also wish to mention our recent data of generation of common marmoset transgenic models of neurodegenrerative diseases, including Parkinson disease, Alzheimer disease and ALS. Furthermore, we have done the deep sequencing of marmoset whole genome with NGS (Sato et al., Sci Rep, 2015) could generate knock-out technologies of common marmoset using genome editing technologies for the generation of transgenic marmoset model of autism and psychiatric disorders. At the end, I will mention about Brain Mapping Projects in Japan, in which investigation of common marmoset brains plays key roles (Okano et al. Neuron, 2016; Kondo et al., Cell Reports, 2018; Lin et al., eLife, 2019).