Modeling neurodegenerative diseases by human pluripotent stem cell-induced brain organoid

Abstract

Neurodegenerative disease (ND) contains a range of conditions which are primarily characterized by progressive neuronal dysfunction and loss. ND is particularly difficult to cure, due to the vulnerability of the nervous system. Currently, few genes and pathways are found to be related to ND. However, no solitary mechanism appears to be primary in neurodegeneration, and these pathogenic mechanisms likely act synergistically through complex interactions to promote neurodegeneration. Moreover, the existing treatment is mainly focusing on alleviating the symptoms of the disease. Furthermore, recent studies reveal considerable overlaps of symptomatology and genetic risks across the disease subtypes by detailed studies at cellular, molecular and genetic level. To better understand the etiology and pathogenesis of ND, study of the abnormalities at patient level is most ideal. However, direct access to the brain tissues from healthy individuals and patients is very limited. Therefore, an alternative experimental model is required to study the mechanism of ND. The most commonly used models are animal models, including Caenorhabditis elegans, Drosophila, zebrafish, and genetically modified mice. However, animal models also have their limitations including partial recapitulation of the disease features and difficulties in modifying disease genes. The recent development in three-dimensional (3D) brain organoids might provide a better experimental model to study ND, because 3D brain organoid system carries great potential to expand the range of both physiological and pathological features that can be found during the development of disease, enabling higher order investigation of mechanism and functionality.