Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration.

Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene.

Toxic interactions between dopamine, α-synuclein, monoamine oxidase, and genes in mitochondria of Parkinson's disease.

Parkinson's disease is characterized by its distinct pathological features; loss of dopamine neurons in the substantia nigra pars compacta and accumulation of Lewy bodies and Lewy neurites containing modified α-synuclein. Beneficial effects of L-DOPA and dopamine replacement therapy indicate dopamine deficit as one of the main pathogenic factors. Dopamine and its oxidation products are proposed to induce selective vulnerability in dopamine neurons.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy.

Disease-modifying treatment of Parkinson's disease by phytochemicals: targeting multiple pathogenic factors.

Parkinson's disease is characterized by typical motor symptoms, loss of dopamine neurons in the substantia nigra, and accumulation of Lewy body composed of mutated α-synuclein. However, now it is considered as a generalized disease with multiple pathological features. Present available treatments can ameliorate symptoms at least for a while, but only a few therapies could delay progressive neurodegeneration of dopamine neurons.

Rasagiline and selegiline modulate mitochondrial homeostasis, intervene apoptosis system and mitigate α-synuclein cytotoxicity in disease-modifying therapy for Parkinson's disease.

Parkinson's disease has been considered as a motor neuron disease with dopamine (DA) deficit caused by neuronal loss in the substantia nigra, but now proposed as a multi-system disorder associated with α-synuclein accumulation in neuronal and non-neuronal systems. Neuroprotection in Parkinson's disease has intended to halt or reverse cell death of nigro-striatal DA neurons and prevent the disease progression, but clinical studies have not presented enough beneficial results, except the trial of rasagiline by delayed start design at low dose of 1 mg/day only. Now strategy of disease-modifying therapy should be reconsidered taking consideration of accumulation and toxicity of α-synuclein preceding the manifest of motor symptoms.

Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure.

In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not only to produce energy and reactive oxygen species. Oxidative stress, deficit of neurotrophic factors, and multiple other factors impair mitochondrial function and induce cell death.

Modification of α-synuclein by lipid peroxidation products derived from polyunsaturated fatty acids promotes toxic oligomerization: its relevance to Parkinson disease.

Recently, toxic α-synuclein oligomer, which can mediate cell-to-cell propagation is suggested to cause sporadic Parkinson disease. α-Synuclein interacts with membrane lipids especially polyunsaturated fatty acids to stabilize its three-dementional structure. Peroxidation of polyunsaturated fatty acids may reduce their affinity to α-synuclein and peroxidation byproducts might modify α-synuclein.

Type A and B monoamine oxidases distinctly modulate signal transduction pathway and gene expression to regulate brain function and survival of neurons.

Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.

Neurotrophic function of phytochemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intracellular signaling and gene expression.

Bioactive compounds in food and beverages have been reported to promote health and prevent age-associated decline in cognitive, motor and sensory activities, and emotional function. Phytochemicals, a ubiquitous class of plant secondary metabolites, protect neuronal cells by interaction with cellular activities, in addition to the antioxidant and anti-inflammatory function. In aging and age-associated neurodegenerative disorders, phytochemicals protect neuronal cells by neurotrophic factor-mimic activity, in addition to suppression of apoptosis signaling in mitochondria.

Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline.

Type B monoamine oxidase (MAO-B) in glial cells has been considered to be associated with neuronal death in Parkinson's disease. MAO-B inhibitors, rasagiline and selegiline [(-)deprenyl], protect neurons in animal and cellular models of neurodegeneration. However, the role of MAO-B itself in the regulation of cell death processing remains elusive, whereas type A MAO (MAO-A) mediates the induction of anti-apoptotic Bcl-2 genes by rasagiline and selegiline.

Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: from neurotransmitter imbalance to impaired neurogenesis.

Type A monoamine oxidase (MAOA) catabolizes monoamine transmitters, serotonin, norepinephrine and dopamine, and plays a major role in the onset, progression and therapy of neuropsychiatric disorders. In depressive disorders, increase in MAOA expression and decrease in brain levels of serotonin and norepinephrine are proposed as the major pathogenic factors. The functional polymorphism of MAOA gene and genes in serotonin signal pathway are associated with depression.

Phytochemicals prevent mitochondrial membrane permeabilization and protect SH-SY5Y cells against apoptosis induced by PK11195, a ligand for outer membrane translocator protein.

Epidemiological studies present the beneficial effects of dietary habits on prevention of aging-associated decline of brain function. Phytochemicals, the second metabolites of food, protect neuronal cells from cell death in cellular models of neurodegenerative disorders, and the neuroprotective activity has been ascribed to the anti-oxidant and anti-inflammatory functions. In this paper, the cellular mechanism of neuroprotection by phytochemicals was investigated, using the cellular model of mitochondrial apoptosis induced by PK11195, a ligand of outer membrane translocator protein, in SH-SY5Y cells.

Rasagiline prevents cyclosporine A-sensitive superoxide flashes induced by PK11195, the initial signal of mitochondrial membrane permeabilization and apoptosis.

Rasagiline, a neuroprotective inhibitor of type B monoamine oxidase, prevented PK111195-induced apoptosis in SH-SY5Y cells through inhibition of mitochondrial apoptosis signaling (J Neural Transm 120:1539-1551, 2013, J Neural Transm 122:1399-1407, 2015). This paper presents that PK11195 induced superoxide flashes, the transit production burst, mediated by cyclosporine A-sensitive membrane permeability transition. Rasagiline prevented superoxide flashes, calcium efflux, and cell death by PK11195.

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

In Parkinson's disease, impaired function of mitochondrial complex I is involved in selective degeneration of dopamine neurons in the substantia nigra. Mitochondria are now considered to play an active role in neuronal death process through activating "intrinsic" apoptotic signaling, in addition to production of reactive oxygen species. This paper presents our recent findings on new functions of mitochondria in regulation of their redox state and function through reversible "S-glutathionylation", a mixed disulfide binding between sulfhydryl groups of GSH and protein cysteine in complex I subunits.

Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells.

Neuromelanin (NM)-containing dopaminergic neurons in the substantia nigra are selectively vulnerable in Parkinson's disease (PD), suggesting the involvement of NM in the pathogenesis. NM is composed of protein, lipid, trace metals and melanin component, a mixture of eumelanin produced from dopamine (DA)-quinone and pheomelanin containing 5-S-cyteinyl-DA-quinone. We reported that NM induces mitochondria-mediated apoptosis in human dopaminergic SH-SY5Y cells, which was suppressed completely by Protease K-treatment, suggesting the essential requirement for the protein component.

Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component.

Parkinson's disease (PD) is characterized by selective depletion of nigral dopamine (DA) neurons containing neuromelanin (NM), suggesting the involvement of NM in the pathogenesis. This study reports induction of apoptosis by NM in SH-SY5Y cells, whereas protease-K-treated NM, synthesized DA- and cysteinyl dopamine melanin showed much less cytotoxicity. Cell death was mediated by mitochondria-mediated apoptotic pathway, namely collapse of mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3, but Bcl-2 over-expression did not suppress apoptosis.

Oxidative stress in mitochondria: decision to survival and death of neurons in neurodegenerative disorders.

In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson's and Alzheimer's disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone, in human dopaminergic SH-SY5Y cells.

Mitochondrial genome variation in eastern Asia and the peopling of Japan.

To construct an East Asia mitochondrial DNA (mtDNA) phylogeny, we sequenced the complete mitochondrial genomes of 672 Japanese individuals (http://www.giib.or.

N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor.

N-Propargyl-l(R)-aminoindan, rasagiline, an anti-Parkinson drug, was found to increase the protein and mRNA levels of glial cell line-derived neurotrophic factor (GDNF) in human neuroblastoma SH-SY5Y cells, whereas an analogue without a propargyl residue, aminoindan, did not. GDNF is known to protect dopaminergic neurons in animal and cellular models of Parkinson's disease, and the supplement has been tried for the treatment of degenerating dopamine neurons in Parkinsonian patients. In this paper, intracellular mechanism underlying the induction of GDNF was studied.

An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells.

In Parkinson's disease, characteristic pathological features are the cell death of nigrostriatal dopamine neurons and the formation of Lewy bodies composed of oxidized proteins. Mitochondrial dysfunction and aggregation of abnormal proteins have been proposed to cause the pathological changes. However, the relation between these two factors remains to be clarified.

Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan.

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, DeltaPsim, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of DeltaPsim. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis.

An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells.

N-Propargyl-1(R)-aminoindan (rasagiline) is now under phase III clinical trials for Parkinson's disease (PD), and it rescues dopamine neurons from cell death in animal and cellular models of PD. Recently, we proved that rasagiline protected dopaminergic SH-SY5Y cells against apoptosis induced by a dopaminergic neurotoxin, N-methyl(R)salsolinol, and the mechanism was clarified to be due to suppression of death signal transduction in mitochondria. In this paper, the effects of rasagiline on the levels of anti-apoptotic bcl-2 gene family were studied.

Glyceraldehyde-3-phospate dehydrogenase is translocated into nuclei through Golgi apparatus during apoptosis induced by 6-hydroxydopamine in human dopaminergic SH-SY5Y cells.

6-Hydroxydopamine is a neurotoxin specific to dopamine neurons, and this neurotoxin at 20 muM was confirmed to induce mainly apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. During the apoptotic process, translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) into nuclei was observed, which is now proposed as an apoptogenic signal in various types of apoptosis. However, it remains to be clarified, how GAPDH is translocated into nuclei.