Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival

Naoi, Makoto; Maruyama, Wakako; Yi, Hong; Inaba, Keiko; Akao, Yukihiro; Shamoto-Nagai, Masayo

doi:10.1007/s00702-009-0309-7

Cited by 68 publications

(43 citation statements)

References 94 publications

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“…The precise mechanisms of MAO-mediated regulation of cellular signaling cascades have not been explored in detail. A potential effector molecule is hydrogen peroxide, which is generated by MAO activity and affects both mitochondrial function and the cellular redox state (35,36). On one hand, mitochondrial dysfunction is a feature of the intrinsic pathway of cell death signaling and is paralleled by increased lipid peroxidation of the mitochondrial membranes (37).…”

Section: Discussionmentioning

confidence: 99%

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Wang

Borchert

Ugun-Klusek

et al. 2011

Journal of Biological Chemistry

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Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression R1 was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin D1 levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development.

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Section: Discussionmentioning

confidence: 99%

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Wang

Borchert

Ugun-Klusek

et al. 2011

Journal of Biological Chemistry

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“…Neuroprotective and neurorestoration strategies addressed to specific bioenergetic defects might hold particular promise in the treatment of spinocerebellar conditions. Drugs, such as rasagiline, have proved efficient in protecting neuronal cells against apoptosis through induction of pro-survival Bcl-2 and neurotrophic factors [129]. Recent alterations of the insulin growth factor (IGF-1) pathway have been reported to be implicated in both SCA1 and SCA7 [130], suggesting that in vivo neuroprotection exerted by IGF-1 through the PP2-regulated PI3K/Akt signalling pathway, could potentially be used to halt cerebellar neurodegeneration [131,132].…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

et al. 2009

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The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.

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“…However, our data indicate that when 5-HT levels are artificially elevated in wild type embryos, which express normal levels of MAO-A, additional signaling events may be triggered. For instance, the MAO reaction releases hydrogen peroxide and aldehydes, which subsequently may activate/inactivate signaling events (29,53). In fact, aldehydes produced by MAO activity have been suggested to cause neuronal cell death (54,55).…”

Section: Discussionmentioning

confidence: 99%

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

Wang¹,

Man

Chu

et al. 2014

Journal of Biological Chemistry

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Background: Monoamine oxidase A (MAO-A) catalyzes the degradation of neurotransmitters such as serotonin. Results: Knockdown of MAO-A expression in embryos induces high serotonin levels and abnormal brain development, which can be rescued by inactivation of serotonin receptor-6 (5-Htr6). Conclusion: 5-Htr6 activation is vital for early development of the embryonic brain. Significance: Serotonin signaling and metabolism are important in early embryos.

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Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival

Cited by 68 publications

References 94 publications

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

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