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 psychosis, an acute symptom, involves striatal hyperdopaminergia that can be treated by dopamine receptor antagonists (e.g. neuroleptics), the underlying pathology leading to these neurotransmitter changes and also the chronic, lifelong impairments of cognitive dysfunction are unknown and currently escape efficient pharmacotherapy.
A common feature of dysfunctional neurons is a disturbance in proteostasis which leads to the protein misassembly and aggregation in the classical neurodegenerative diseases. More subtle disturbances in proteostasis equally lead to protein misassembly and aggregation as a signature of biological subsets of chronic mental diseases – even though not causing neurotoxicity - which can be analyzed to molecular detail and modeled in vitro and in vivo.
The Korth laboratory has pioneered the notion of protein misassembly and aggregation in chronic mental diseases and is currently translating these insights into improved diagnostics and therapies (Bradshaw & Korth, Vimeo, YouTube).
In the last decade we have demonstrated the occurrence of several specific, insoluble proteins in subsets of postmortem brains of patients with chronic mental diseases by biochemical methods: Disrupted-in schizophrenia 1 (DISC1), Collapsin response mediator protein 1 (CRMP1), dysbindin and Trio and F-actin Binding Protein isoform 1 (TRIOBP1). These findings are evidence of aberrant proteostasis in the brains of subsets of patients with schizophrenia or recurrent affective disorders, leading to aberrant protein assembly and signaling.
Most detailed molecular analyses and translational studies were conducted on the DISC1 protein. In vitro, we demonstrated cell invasiveness and transmissibility and the induction of endogenous DISC1aggregates by infection with influenza virus.
A transgenic rat model modestly overexpressing full length, non-mutant human DISC1 mimics DISC1 protein pathology observed in schizophrenia postmortem brains and shows aberrant dopamine homeostasis, thus reflecting a major disease state of schizophrenia. It also displays aberrant neuroanatomical architecture of the dopaminergic system, as well as cognitive and social deficits compatible with schizophrenia-like symptoms (see also Publication, publication, publication, publication, publication).
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 (Link; see accompanying video clip).
The Korth laboratory is embedded in many longstanding scientific and clinical collaborations pursuing molecular psychiatry research and Carsten Korth has coordinated two European research networks on molecular psychiatry: NEURON-ERANET DISCover and MSCA-ITN IN-SENS.