Clinical issue
There is an urgent need to develop new approaches for studying brain diseases to investigate the complex gene-environment interactions that contribute to their pathology. Schizophrenia (SZ), which is thought to be a disorder of brain development, is a life-long mental illness affecting ∼1% of the world’s population. Despite heritability being estimated at 80%, with family history the most important risk factor, genetic family and association studies have failed to reveal causative genes for the disease. Parkinson’s disease (PD) is a degenerative neurological disorder affecting 0.1% of the world’s population. Its prevalence is age-dependent, increasing to 2% of individuals over 60 years of age. This complex brain disease has genetic and environmental risk factors that impact mitochondrial function, oxidative stress and xenobiotic metabolism. Mutations in several genes cause inherited PD, although these account for <5% of cases. It is hoped that new approaches for studying brain diseases such as SZ and PD will reveal common steps in heterogeneous aetiological processes that could be targets for therapeutic intervention. Post-mortem brain samples provide some insights, but enable the identification of endpoints of disease only and are limited in supply. Other patient-derived cell types, such as fibroblasts and lymphoblastoid cell lines, are easily accessible but, because they are non-neural cells, they might lack important features necessary for understanding the biological bases of brain diseases.
Results
In this paper, the authors present a new patient-cell-based model for investigating brain diseases. They derive and culture cells from the olfactory mucosa, the sense organ of smell, which contains stem cells that continually regenerate the organ’s sensory neurons throughout adult life. The authors use this model to identify the genes, proteins and cellular functions that are altered in cells derived from patients with SZ and PD by comparing them with cells derived from healthy controls. This approach demonstrates disease-specific differences in gene expression, protein expression and cell function that are in line with current theories regarding the aetiologies of SZ and PD. In cells derived from patients with SZ, the authors identify dysregulation in cell signalling pathways of brain development, some of which have previously been identified as candidates for disease susceptibility (such as Reelin signalling, VDR/RXR activation, IL-8 signalling, glutathione metabolism and ErbB signalling). Importantly, fibroblasts derived from patients with SZ did not show these differences. In cells derived from patients with PD, the authors identify marked changes in signalling pathways involved in oxidative stress and xenobiotic metabolism (such as the NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signalling, glutathione metabolism and xenobiotic metabolism signalling). Furthermore, the authors uncover new specific molecular and genetic pathways that might expand our understanding of disease aetiology and advance therapeutic development.
Implications and future directions
The capacity to tease out disease-specific differences using this patient-cell-based model provides specific candidate genes and cell pathways for future studies of brain diseases. In addition to providing informative data on SZ and sporadic PD, this model might be useful for studying the cellular and molecular bases of other neurological conditions. This system can be applied to improve our understanding of disease aetiology, the development of new diagnostics and drug discovery.