The neurobiology of chronic mental diseases like schizophrenia or the recurrent affective disorders is still poorly understood. In schizophrenia, for example, acute and chronic symptoms are known; whereas the psychosis involves striatal hyperdopaminergia and can be treated by dopamine antagonists, the underlying pathology leading to these neurotransmitter changes and also the chronic, lifelong impairments of cognitive dysfunction are unknown and escape efficient pharmacotherapy.
A common feature of dysfunctional neurons is a disturbance in proteostasis which leads to the protein deposition and aggregation in the classical neurodegeneartive diseases. While chronic mental diseases are clearly no neurodegenerative diseases, the identification of subtle alterations in proteostasis may equally lead to subtle protein aggregates in the chronic mental diseases which then can serve as a handle to further investigate the molecular mechanisms of fundamental neuronal dysfunction. The Korth laboratory has developed technology for investigating how subtle developmental changes in neuronal migration can affect adult neuropathology and behavior (see video).
Carsten Korth's laboratory has pioneered the notion of misfolded proteins in chronic mental diseases (Interview of International Innovation with Carsten Korth from July 2012 on Mental illness Research; recent review: Bradshaw & Korth, Mol Psychiatry, in press) by demonstrating that insoluble DISC1 protein occurs in post mortem brain tissue of patients with chronic mental disorders, and that disease associated polymorphisms increase the tendency of DISC1 to form oligomers (Leliveld, J Neurosci, 2008; Leliveld, 2009; Seshadri, PNAS 2010). Furthermore, cell invasiveness of DISC1 aggregates (Ottis, Biol Psychiatry 2011; video on The Journal of Visual Experimentation) and their cell-to-cell transmissibility was demonstrated (Zhu, Open Biol 2017) indicating that certain psychiatric diseases might be classified as protein conformational diseases (OpenAccess Review: Korth, Prion 2012; Bradshaw & Korth, Mol Psychiatry, in press), and thus display overlap in disease pathomechanisms with neurodegenerative diseases.
A transgenic rat model modestly overexpressing full length, non mutant human DISC1 is the first reverse eningeered rat model of of a major mental illness gene. It mimics protein pathology and shows aberrant dopamine homeostasis, thus reflecting a major disease state of schizophrenia (Trossbach, Bader et al., 2016, Molecular Psychiatry). It also displays aberrant neuroanatomical architecture of the dopaminergic system (Hamburg, Sci Rep, 2016), as well as cognitive deficits compatible with schizophrenia-like symptoms (Wang, Neurobiol Learn Mem, 2017; Kaefer, Hippocampus, in press; Wang, Pharmacol Biochem Behav, 2019). Using this animal model, in a reverse-translational approach we have identified similar blood markers in the tgDISC1 rat and a subset of schizophrenia patients opening the possibility of a blood test for this subset of patients (Trossbach, Translational Psychiatry, 2019; see accompanying videoclip here).
Using the novel technique of epitope discovery and an interdisciplinary approach, CRMP1 (Bader, Hum Mol Genet 2012) and TRIOBP1 (Bradshaw et al., 2014, PloS ONE) were identified as a candidate proteins in chronic mental illnesses.
Carsten Korth is currently coordinating a European research consortium IN-SENS (Inter and intracellular signaling in schizophrenia; www.in-sens.eu) on cutting edge research in the biological classification of schizophrenia (see also videos at vimeo or youtube).