ArticleThe Journal of clinical investigation2017
Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
- Epigenetic Evidence Implies Disturbed Proteostasis and Potentially Protein Aggregation in Suicidality.Biomolecules · 2026Review
- Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients.Molecular psychiatry · 2025Article
- Tracing the aggregation pathway of the scaffold protein DISC1: Structural implications for chronic mental illnesses.Journal of structural biology: X · 2025Article
- Amlexanox Ameliorates Traumatic Brain Injury by Restoring Autophagy-Lysosomal Function via cAMP Signaling Modulation.International journal of biological sciences · 2025Article
- Long noncoding RNAs in ubiquitination, protein degradation, and human diseases.Biochimica et biophysica acta. Gene regulatory mechanisms · 2024Review
- The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.Cells · 2024Review
- Article
- Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.Molecular psychiatry · 2022Article
- A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.Biological psychiatry · 2022Review
- Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses.Translational psychiatry · 2021Article
- The Emerging Role of Phosphodiesterases in Movement Disorders.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.Molecular psychiatry · 2021Article
- A role of cellular translation regulation associated with toxic Huntingtin protein.Cellular and molecular life sciences : CMLS · 2020Article
- Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders.Biological psychiatry · 2020Review
- Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice.Neuroscience research · 2020Article
- Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness.Molecular psychiatry · 2019Review
- [Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2019Article
- GSK3β negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons.Molecular psychiatry · 2018Article
- TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration.Biological psychiatry · 2018Article
- Mechanisms of protein toxicity in neurodegenerative diseases.Cellular and molecular life sciences : CMLS · 2018Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
Abstract
Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.
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Registered trials
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