ArticleMolecular psychiatry2016
Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.
Article in Molecular psychiatry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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Who cites it
58 citing papers in PubMed, 2 syntheses or guidelines pooled it, 89 citations in OpenAlex.
- Hubs of long-distance co-alteration characterize brain pathology.Human brain mapping · 2020Pooled it
- The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review.Translational psychiatry · 2017Pooled it
- Widespread synaptic density loss in schizophrenia follows molecular and network architecture.Molecular psychiatry · 2026Article
- Targeting endoplasmic reticulum stress and protein misfolding in schizophrenia: the emerging promise of sigma-1 receptor agonists.Psychopharmacology · 2026Review
- Epigenetic Evidence Implies Disturbed Proteostasis and Potentially Protein Aggregation in Suicidality.Biomolecules · 2026Review
- Levels of aggregation of proteins related to mental illness, assayed by insolubility, vary across the brains of individuals.Scientific reports · 2026Article
- Pharmacological rescue of social deficits in rats featuring Disrupted-in-Schizophrenia-1 (DISC1) protein aggregation.Schizophrenia (Heidelberg, Germany) · 2026Article
- DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy.Nature communications · 2025Article
- Social Reward Learning Deficits and Concordant Brain Alterations in Rats Overexpressing Disrupted-in-Schizophrenia 1 (DISC1).The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients.Molecular psychiatry · 2025Article
- Peering into the mind: unraveling schizophrenia's secrets using models.Molecular psychiatry · 2025Review
- Dysregulation of myelination-related genes in schizophrenia.Journal of neurochemistry · 2024Review
- TransgenicCurrent issues in molecular biology · 2024Article
- Highly sensitive and simultaneous detection of ascorbic acid, dopamine, and uric acid using Pt@g-CiScience · 2024Article
- 50-kHz ultrasonic vocalizations do not signal social anhedonia in transgenic DISC1 rats.Brain and behavior · 2023Article
- Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.International journal of molecular sciences · 2022Review
- TRIOBP-1 Protein Aggregation Exists in Both Major Depressive Disorder and Schizophrenia, and Can Occur through Two Distinct Regions of the Protein.International journal of molecular sciences · 2022Article
- Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in HeterozygousInternational journal of molecular sciences · 2022Article
- Social anhedonia as a Disrupted-in-Schizophrenia 1-dependent phenotype.Scientific reports · 2022Article
- A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.Biological psychiatry · 2022Review
Corrections and comments
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Authors and funding
30 authors at 9 institutions in 4 countries.
Funding
Abstract
Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.
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Registered trials
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