A model of the mitochondrial basis of bipolar disorder

Morris, Gerwyn; Walder, Ken; McGee, Sean L.; Dean, Olivia; Tye, Susannah J.; Maes, Michaël; Berk, Michael

doi:10.1016/j.neubiorev.2017.01.014

Cited by 136 publications

(124 citation statements)

References 393 publications

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“…Oxidative stress secondary to mitochondrial dysfunction is also implicated in BD pathophysiology [125]. In a meta-analysis, oxidative stress markers were observed to be increased in BD [126].…”

Section: Downstream Targets Of Pkcmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

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Section: Downstream Targets Of Pkcmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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“…Prolonged and severe oxidative stress leads to the activation of GSK-3 [262][263][264]; its physiological levels of expression and activity play an indispensable role in the regulation of synaptic function and other aspects of neurotransmission as well as levels of tau phosphorylation [12,265]. Given this information, the presence of data implicating dysregulation in the activity of the two isoforms of this kinase as one cause of synaptic dysfunction in MCI and AD is unsurprising (reviewed by [266]).…”

Section: Increased Oxidative Stress and Altered Gsk-3 Activity In Ad mentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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“…These include alterations in the metabolism and action of cholinergic [14], glutaminergic [15], GABAergic [16], and opioid [17] neurotransmission as well as changes in the activity of proteins located at the post-synaptic densities [18]. In addition, strong evidence showed that mitochondrial function [19,20] and oxidative stress [21] and inflammation [22,23] participate in the etiology of BD: Reduced antioxidant capacity was described in bipolar patients, manifested by decreased levels of glutathione in post-mortem prefrontal cortex samples [24]. Downregulation of a number of antioxidant genes, including Superoxide dismutase (SOD1), was found in BD [25].…”

Section: Depressive and Bipolar Disorder (Bd)mentioning

confidence: 99%

Na+, K+-ATPase Signaling and Bipolar Disorder

Lichtstein¹,

Ilani²,

Rosen³

et al. 2018

IJMS

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Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.

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A model of the mitochondrial basis of bipolar disorder

Cited by 136 publications

References 393 publications

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Na+, K+-ATPase Signaling and Bipolar Disorder

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