Disrupted‐in‐schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first‐episode psychosis

Author:

Pils Marlene12ORCID,Rutsch Julia3,Eren Feride4,Engberg Göran4,Piehl Fredrik56,Cervenka Simon78,Sellgren Carl47,Troßbach Svenja3,Willbold Dieter129,Erhardt Sophie4,Bannach Oliver12,Korth Carsten3ORCID

Affiliation:

1. Institute of Biological Information Processing (Structural Biochemistry: IBI‐7) Forschungszentrum Jülich Jülich Germany

2. attyloid GmbH Düsseldorf Germany

3. Department of Neuropathology Heinrich Heine University of Düsseldorf Düsseldorf Germany

4. Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

5. Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

6. Department of Neurology Karolinska University Hospital Stockholm Sweden

7. Centre for Psychiatry Research, Department of Clinical Neuroscience Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm Stockholm Sweden

8. Department of Medical Sciences, Psychiatry Uppsala University Uppsala Sweden

9. Institut für Physikalische Biologie Heinrich‐Heine‐Universität Düsseldorf Düsseldorf Germany

Abstract

AimThe disrupted‐in‐schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first‐episode psychosis (FEP).MethodCerebrospinal fluid samples of patients with FEP (n = 50) and matched healthy controls (HCs; n = 47) were measured by the highly sensitive surface‐based fluorescence intensity distribution analysis technology that enables single aggregate detection.ResultsWe demonstrate that DISC1 protein aggregates are increased in cerebrospinal fluid samples of patients with FEP versus HCs. The concentration was in the low femtomolar range. No correlations were found with specific symptom levels, but the difference was particularly significant in the subset of patients with the diagnoses schizophrenia, unspecified (DSM‐IV 295.9) or schizoaffective disorder (DSM‐IV 295.70) at 18‐month follow‐up. DISC1 protein aggregate levels did not significantly change within the 18‐month observation interval and were on average higher for individuals carrying the major DISC1 rs821577 allele, before correction.ConclusionThe occurrence of protein aggregates in vivo in patients with psychotic disorders has not been previously reported. It underscores the significance of posttranslational modifications of proteins both as pathogenetic mechanisms and as potential diagnostic markers in these disorders.

Funder

ALS Association

Deutsche Forschungsgemeinschaft

Michael J. Fox Foundation for Parkinson's Research

Vetenskapsrådet

Weston Brain Institute

Publisher

Wiley

Subject

Psychiatry and Mental health,Neurology (clinical),Neurology,General Medicine,General Neuroscience

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