Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression

Pfaffenseller, Bianca; Wollenhaupt-Aguiar, Bianca; Fries, Gabriel R.; Colpo, Gabriela Delevati; Burque, Renan Kubiachi; Bristot, Giovana; Ferrari, P.; Ceresér, Keila Maria Mendes; Rosa, Adriane Ribeiro; Klamt, Fábio; Kapczinski, Flávio

doi:10.1017/s1461145714000443

Cited by 63 publications

(53 citation statements)

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“…DDIT3 is a key modulator of the unfolded protein response activated by the endoplasmic reticulum (ER) stress. This finding was also supported by the literature, with several studies suggesting a key role of ER stress in BD (Hayashi et al, 2009; Pfaffenseller et al, 2014; So et al, 2007), including the effects of lithium on LCLs (Breen et al, 2016). …”

Section: Discussionsupporting

confidence: 82%

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Fries

Colpo

Monroy-Jaramillo

et al. 2017

European Neuropsychopharmacology

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Lithium is the most commonly prescribed medication for the treatment of bipolar disorder (BD), yet the mechanisms underlying its beneficial effects are still unclear. We aimed to compare the effects of lithium treatment in lymphoblastoid cell lines (LCLs) from BD patients and controls. LCLs were generated from sixty-two BD patients (based on DSM-IV) and seventeen healthy controls matched for age, sex, and ethnicity. Patients were recruited from outpatient clinics from February 2012 to October 2014. LCLs were treated with 1 mM lithium for 7 days followed by microarray gene expression assay and validation by real-time quantitative PCR. Baseline differences between groups, as well as differences between vehicle- and lithium-treated cells within each group were analyzed. The biological significance of differentially expressed genes was examined by pathway enrichment analysis. No significant differences in baseline gene expression (adjusted p-value < 0.05) were detected between groups. Lithium treatment of LCLs from controls did not lead to any significant differences. However, lithium altered the expression of 236 genes in LCLs from patients; those genes were enriched for signaling pathways related to apoptosis. Among those genes, the alterations in the expression of PIK3CG, SERP1 and UPP1 were validated by real-time PCR. A significant correlation was also found between circadian functioning and CEBPG and FGF2 expression levels. In summary, our results suggest that lithium treatment induces expression changes in genes associated with the apoptosis pathway in BD LCLs. The more pronounced effects of lithium in patients compared to controls suggest a disease-specific effect of this drug.

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Section: Discussionsupporting

confidence: 82%

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Fries

Colpo

Monroy-Jaramillo

et al. 2017

European Neuropsychopharmacology

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“…Also, changes in the levels of several ER UPR-related proteins have been described in BD. In healthy controls but not in BD patients it was found an increase in the levels of GRP78, eIF2α-P, and CHOP after ER stress induction, which represents a cellular response to inhibit global protein synthesis and, therefore, functions as a defense mechanism triggered to cope with stress and restore ER homeostasis [19]. Tunicamycin-induced cell death was found significantly higher in patients compared to controls and, more importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response [19].…”

Section: Functional Outcomementioning

confidence: 89%

“…In healthy controls but not in BD patients it was found an increase in the levels of GRP78, eIF2α-P, and CHOP after ER stress induction, which represents a cellular response to inhibit global protein synthesis and, therefore, functions as a defense mechanism triggered to cope with stress and restore ER homeostasis [19]. Tunicamycin-induced cell death was found significantly higher in patients compared to controls and, more importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response [19]. These findings are in accordance with the "MAM hypothesis" for BD pathophysiology (Figure 1), which hypothesizes that ER-mitochondria miscommunication at MAMs is an initial event diminishing cellular resilience to stressful conditions in BD patients.…”

mentioning

confidence: 89%

“…It has many different functions including the translocation of proteins across the ER membrane, the integration of proteins into the membrane, the folding and modification of proteins in the ER lumen, the synthesis of phospholipids and steroids on the cytosolic side of the ER membrane, and the storage of Ca 2+ ions in the ER lumen and their regulated release into the cytosol [19,33]. Lately, ER has been put forward as a key organelle in inducing chronic stress associated with many brain disorders including neuropsychiatric diseases such as BD [58].…”

Section: Compromised Er Stress Responsementioning

confidence: 99%

“…The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium. Furthermore, patient-derived cellular models also support that alterations in microRNAs (miRNAs), glia and immune cell signaling, cytoskeleton as well as oxidative stress, inflammasome activation, autophagy and apoptosis play a relevant role in BD pathophysiology [8,[19][20][21][22][23][24][25][26][27][28][29]. …”

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confidence: 99%

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The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Pereira¹,

Resende²,

Morais³

et al. 2017

IJCNMH

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Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca 2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the "MAM hypothesis" for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity. Bipolar DisorderBD is a chronic psychiatric illness with a remitting course, affecting 2.4% of the general population [1], characterized by mood swings between manic and depressive states that result in cognitive and functional impairments, high health care costs and premature mortality [2,3]. BD is the sixth leading cause of disability worldwide responsible for loss of more disability-adjusted life-years than all forms of cancer and major neurological conditions [4]. BD is associated with greatly impaired quality of life and increased physical health burden [5]. Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowl...

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Genotype–phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype

Gordon‐Smith

Green

Grozeva

et al. 2018

American J of Med Genetics Pt B

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Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca 2+ ATPase Isoform 2 (SERCA2). Evidence of a population-level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotypephenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype-phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features.Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p = .011). We also found a significant relationship between mutations located in the S4-M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p = .032).Our findings add support to the hypothesis that Darier-causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness. K E Y W O R D SDarier disease, genotype-phenotype correlations, neuropsychiatric features

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Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression

Cited by 63 publications

References 53 publications

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Genotype–phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype

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