Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview

Abstract

Schizophrenia (SCZ) is a highly heritable, polygenic neuropsychiatric disease, which disables the patients as well as decreases their life expectancy and quality of life. Common and Rare variants studies on SCZ subjects have provided more than 100 genomic loci that hold importance in the context of SCZ pathophysiology. Transcriptomic studies from clinical samples have informed about the differentially expressed genes (DEGs) and non-coding RNAs in SCZ patients. Despite these advancements, no causative genes for SCZ were found and hence SCZ is difficult to recapitulate in animal models. In the last decade, induced Pluripotent Stem Cells (iPSCs)-based models have helped in understanding the neural phenotypes of SCZ by studying patient iPSC-derived 2D neuronal cultures and 3D brain organoids. Here, we have aimed to provide a simplistic overview of the current progress and advancements after synthesizing the enormous literature on SCZ genetics and SCZ iPSC-based models. Although further understanding of SCZ genetics and mechanisms using these technological advancements is required, the recent approaches have allowed to delineate important cellular mechanisms and biological pathways affected in SCZ.

Upregulated extracellular matrix-related genes and impaired synaptic activity in dopaminergic and hippocampal neurons derived from Parkinson’s disease patients withPINK1andPARK2mutations

“…The primary pathogenic symptom of PD is the loss of DA neurons, so the study of PD using iPSCs focuses on DA neuronal differentiation 25,26 . Previous studies that worked on phenotypic characterization using iPSCs became the platform to establish new paradigms for cellular therapeutic techniques, drug development, and preclinical and clinical study screening [27][28][29][30][31][32][33][34] . In iPSC-derived DA neurons, mutant PARK2 was unable to recruit to PINK1, which reduced dopamine vesicle endocytosis, disrupted microtubule stability, decreased neuronal complexity, increased spontaneous excitatory post-synaptic currents in neurons, and increased dopamine release (although there is still no consensus on this specific point).…”

Editorial: Advances in neural reprogramming, disease modeling and therapeutic insights

“…Neurons derived through the reprogramming of somatic cells and differentiation have been shown to lack aging related signatures and are considered rejuvenated (Mertens et al, 2018). Studies show that even these young neurons carry information that relates to biological differences in the patients' brains (Choudhary et al, 2022;Hussein et al, 2023) and the case of neurodegenerative disease these probably occur long before the disease onset (Stern et al, 2022;Rike and Stern, 2023). However, other studies show also that especially in aging-related diseases, it may be important to use models where the age signatures persist through the differentiation (Mertens et al, 2021;Lau et al, 2022).…”