A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders

Hui, Kelvin; Endo, Ryo; Sawa, Akira; Tanaka, Motomasa

doi:10.1016/j.biopsych.2021.09.001

Cited by 6 publications

(5 citation statements)

References 129 publications

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“…Aberrant proteostasis is a hallmark of aging and neurodegenerative diseases [ 108 , 109 ]. Proteostasis alterations in neuropsychiatric disorders do not result in massive neuronal death, but in diverse loss- and gain-of-function events converging in the disruption of synaptic and neural functions [ 110 – 112 ]. Specific proteases and E3 ubiquitin ligases are mutated in hereditary mental and neurodevelopmental disorders [ 113 – 117 ].…”

Section: Hallmark 3: Recycling and Turnovermentioning

confidence: 99%

The missing hallmark of health: psychosocial adaptation

López-Otín,

Kroemer

2024

CST

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The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health (“psychosocial adaptation”) and as an additional stratum (“psychosocial interactions”), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.

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Section: Hallmark 3: Recycling and Turnovermentioning

confidence: 99%

The missing hallmark of health: psychosocial adaptation

López-Otín,

Kroemer

2024

CST

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“…The establishment of a role of posttranslationally modified proteins, and particularly the identification of candidate proteins, in major psychiatric diseases, is still in its infancy 2,3 . The disrupted-in-schizophrenia 1 (DISC1) gene was identified as a familial gene in a large Scottish pedigree 4 but was subsequently not found to feature in larger studies of common gene variants 1,5 .…”

Section: Mainmentioning

confidence: 99%

Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid are elevated in first-episode psychosis patients

Pils

Rutsch

Eren

et al. 2023

Preprint

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The Disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of 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. Here we demonstrate that DISC1 protein aggregates are increased in CSF samples of patients with first episode psychosis (n=50) compared to healthy controls (n=47), as measured by the highly sensitive surface-based fluorescence intensity distribution analysis technology that enables single aggregate detection. The concentration was in the low femtomolar range. No correlations were found to symptom levels, but the difference was particularly significant in the subset of patients receiving the diagnoses schizophrenia, unspecified (DSM IV 295.9) or schizoaffective disorder (DSM IV 295.70) at 18-month follow-up. The 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.

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“…The establishment of a role of posttranslationally modified proteins, such as misassembled or aggregated proteins, and particularly the identification of candidate proteins in major psychiatric diseases is still in its infancy. 3,4 The disrupted-in-schizophrenia 1 (DISC1) gene was identified as a familial gene in a large Scottish pedigree 5 but was subsequently not found to feature in larger studies of common gene variants. 1,6 The protein, however, is subject to posttranslational modifications such as phosphorylation 7 and multimerization.…”

mentioning

confidence: 99%

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

Pils,

Rutsch,

Eren

et al. 2023

Psychiatry Clin Neurosci

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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 (CSF) samples of patients with FEP (n = 50) and matched healthy controls (HC; n = 47) were measured by the highly sensitive surface‐based fluorescence intensity distribution analysis (sFIDA) technology that enables single aggregate detection.ResultsHere we demonstrate that DISC1 protein aggregates are increased in CSF samples of FEP vs. HC. The concentration was in the low femtomolar range. No correlations were found to specific symptom levels, but the difference was particularly significant in the subset of patients receiving 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 months observation interval, and were in 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.This article is protected by copyright. All rights reserved.

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A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders

Cited by 6 publications

References 129 publications

The missing hallmark of health: psychosocial adaptation

The missing hallmark of health: psychosocial adaptation

Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid are elevated in first-episode psychosis patients

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

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