Naslov
Protein pathology in chronic mental illness-towards a biological definition

Autori
Korth, Carsten ; Bader, Verian ; Trossbach, Svenja ; Marreiros, Rita ; Bradshaw, Nicholas

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Izvornik
Npj Schizophrenia / - , 2016, 160101-2

Skup
5th Biennial SITS conference

Mjesto i datum
Firenca, Italija, 02.04.2016. - 06.04.2016

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
DISC1 ; schizophrenia ; protein aggregation ; TRIOBP

Sažetak
Background: Disruption of proteostasis is a common cellular penotype after a genetic or exogenous lesion of postmitotic neurons. In the most extreme examples, the neurodegenerative diseases, proteostasis disturbance leads to microscopically visible protein deposits. However, it is reasonable to assume that also in other chronic brain conditions, for example mental illnesses like residual schizophrenia or chronic depression, proteostasis occurs, even though clearly not accompanied by massive neuronal loss. The hypothesis of my laboratory was therefore to investigate the occurence of proteostasis in the context of chronic mental illnesses like schizophrenia, exemplified by the occurrence of protein pathology, i.e. proteins insoluble in ionic detergents. Methods: Post mortem brains from patients with schizophrenia, bipolar disorder, depression, or healthy controls were obtained from the Stanley Research Foundation (Consortium collection ; n = 60), and the insoluble proteome purified by biochemical fractionation. The insoluble proteome of each patient was then either immunoblotted for candidate genes or pooled by diagnosis (n = 15) and injected into mice for the generation of monoclonal antibodies that would selectively recognize only schizophrenia brains but not healthy brain (epitope disovery) ; epitopes of such antibodies were determined on protein arrays. Finally, we also performed proteomics of the insoluble proteome. For positive hits, genetic studies were performed to gather independent evidence. Candidate proteins for which misassembly was firmly established animal models were generated by modest overexpression (Molecular Psychiatry, in press). Results: For the rare candidate gene Disrupted-in-Schizophrenia 1 (DISC1), we could show insolubility in a subset of patients with mental illness crossing clinical diagnoses. When we modeled DISC1 aggregation in a novel transgenic rat model, we observed disruption of dopamine homeostasis with amphetamine hypersensitivity aberrant dopamine reuptake (Molecular Psychiatry, in press), validating the notion of DISC1 protein pathology for chronic mental illness. Using epitope discovery we identified two candidate proteins, CRMP1 and TRIOBP1 as aggregated in subsets of cases with chronic mental illness. Proteomics of the insoluble proteome of schizophrenia yielded more novel candidates that are currently validated. Discussion: Protein pathology is a novel way of classifying chronic mental illnesses such as schizophrenia, complementing the currently prevailing genetic view. In fact, in the classical neurodegenerative diseases, the same proteins aggregate in sporadic cases, that are mutant in the minority of familial cases. More specifically, insoluble DISC1 assemblies seem to regulate dopamine homeostasis, a brain central metabolic disturbance during psychosis. Using this transgenic rat model, a number of reverse translational approaches are possible like the identification of diagnostic biomarkers for chronic mental illnesses related to DISC1.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Biotehnologija, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA