Dissecting the mechanisms underlying adolescent-onset schizophrenia using patient-derived cells

Thesis

Schizophrenia is a complex mental disorder with unknown causes. It is widely accepted that the disease has a strong genetic basis and a root in neurodevelopment. To investigate the mechanisms at the cellular and molecular levels of schizophrenia, we collected blood, nasal and skin primary tissues from a cohort of patients with adolescent-onset schizophrenia and healthy controls. Whole exome sequencing revealed genetic variants associated with multiple pathways including cell adhesion and postsynaptic signalling. Patient-derived primary olfactory ecto-mesenchymal stem cells had significantly reduced adhesion and elevated levels of stress responses. Total protein expression profiling showed significantly downregulated EIF signalling, mTOR pathway and cytoskeleton regulation, resulting in reduced global protein synthesis, impaired stress response and dysregulated cytoskeleton dynamics. These observations highly agreed with previously studies on adult-onset schizophrenia, suggesting common disease mechanisms. Induced neurons, reprogrammed from skin fibroblasts via induced pluripotent stem cells, did not reveal obvious differences on neurite outgrowth and spine morphologies. Further studies are required to investigate the synaptic signal transmission of the induced neurons. This study demonstrated the use of human-specific systems to study disease mechanisms and highlighted the potential to discover dynamic disease-associated cellular and molecular phenotypes, as well as some technical challenges.

Authors: Li, Y

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford