Parkinson's disease (PD) is an aging-related disease and the second most common neurodegenerative disease after Alzheimer's disease. The main symptoms of PD are movement disorders accompanied with ...deficiency of neurotransmitter dopamine (DA) in the striatum due to cell death of the nigrostriatal DA neurons. Two main histopathological hallmarks exist in PD: cytosolic inclusion bodies termed Lewy bodies that mainly consist of α-synuclein protein, the oligomers of which produced by misfolding are regarded to be neurotoxic, causing DA cell death; and black pigments termed neuromelanin (NM) that are contained in DA neurons and markedly decrease in PD. The synthesis of human NM is regarded to be similar to that of melanin in melanocytes; melanin synthesis in skin is via DOPAquinone (DQ) by tyrosinase, whereas NM synthesis in DA neurons is via DAquinone (DAQ) by tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). DA in cytoplasm is highly reactive and is assumed to be oxidized spontaneously or by an unidentified tyrosinase to DAQ and then, synthesized to NM. Intracellular NM accumulation above a specific threshold has been reported to be associated with DA neuron death and PD phenotypes. This review reports recent progress in the biosynthesis and pathophysiology of NM in PD.
Keisuke Fujita, M.D., Ph.D. (1925–1995), founded and was President of Fujita Gakuen (academy) in 1964, Fujita Health University in 1968, and Fujita Health University (FHU) School of Medicine in 1972. ...He also established the Institute for Comprehensive Medical Science (ICMS) at FHU in 1972, at the same time as the founding of FHU School of Medicine, to promote the institutional development of FHU School of Medicine by providing a strong foundation for science. I collaborated with Dr. Fujita from 1965. Returning from the study abroad at the NIH in the USA in 1965, I joined Professor Fujita’s Department of Biochemistry at the Aichi Gakuin University School of Dentistry, as an Associate Professor. Dr. Fujita’s major research interest was in the biochemistry of diseases, namely, cancer, neuropsychiatric diseases, and various intractable diseases, which he investigated by applying analytical chemistry and molecular/cellular biochemistry. He was also interested in the pharmacognosy of aloe plants and established “Syoyaku Kenkyu Juku (Center for Pharmacognosy),” and where he studied by himself and trained many FHU graduates. I herein present an overview of the research carried out by Dr. Fujita to share his legacy and praise his memoir and contributions to medical science and education for all faculty members, staffs and students of FHU. It is assumed that individuals at FHU have already made significant contributions to medical science. I hope that his vision of FHU producing a Nobel Prize laureate will be realized someday.
The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially ...vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca
oscillations in the absence of the Ca
-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca
concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca
oscillations, and (3) providing bioenergetic support.
Distinguished Professor Emeritus Tsuneko Okazaki is a hero of science. Together with her late husband, Professor Reiji Okazaki, she discovered that DNA replication involves the discontinuous ...synthesis of the DNA lagging strand by intermediates of, what is now called, “Okazaki fragments.” She has been a pioneer for women in science and, in 1983, became the first female full Professor at Nagoya University. From 1997 to 2012, she was a full Professor and later a Visiting Professor at Fujita Health University, and this review zooms in on that period. Besides a summary of her career, this article also includes personal memories of researchers who worked with Professor Okazaki.
Abstract Dopamine (DA) supplementation therapy by L-dopa for Parkinson's disease (PD) was established around 1970. The dose of L-dopa can be reduced by the combined administration of inhibitors of ...peripheral L-amino acid decarboxylase (AADC), catechol O-methyltransferase (COMT), or monoamine oxidase B (MAO B). DA in the striatum may be produced from exogenously administered L-dopa by various AADC-containing cells, such as serotonin neurons. The long-term administration of L-dopa in PD patients may produce L-dopa–induced dyskinesia (LID), which may be due to chronic overstimulation of supersensitive DA D1 receptors. L-dopa may be used in combination with various new strategies such as gene therapy or transplantation in the future.
Leonor Michaelis spent the years of 1922–1926 as Professor of Biochemistry of the Aichi Medical College (now Graduate School of Medicine, Nagoya University) in Nagoya, Japan. Michaelis succeeded in ...gathering many bright young biochemists from all over Japan into his laboratory, and made tremendous contributions to the promotion of biochemistry in Japan. Michaelis was invited to many places in Japan to present lectures over those years. Kunio Yagi, who was Professor of Biochemistry at Nagoya University in the second half of the 20th century, succeeded in crystallizing the “Michaelis” enzyme–substrate complex. Historically, Michelis has had an enormous impact on biochemistry in Japan.
The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine ...hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson’s disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism
.
DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of
TH, AADC,
and
GCH1
via adeno-associated virus (AAV) vectors.
There are numerous observations confirming that microglia expressing major histocompatibility complex (MHC) class II molecules are associated with the central nervous system (CNS) in aging and ...pathological conditions. In this study, we investigated the distribution of MHC class II-positive microglia in Parkinson's disease (PD) brains. The number of MHC class II-positive microglia in the substantia nigra (SN) and putamen increased as the neuronal degeneration of the SN proceeded. These cells were also ICAM-1 (CD54) and LFA-1 (CD11a) positive. The number of activated microglia not only in the SN and putamen but also in the hippocampus, transentorhinal cortex, cingulate cortex and temporal cortex in PD was significantly higher than that in the normal control. Most activated microglia persisted regardless of the presence or absence of Lewy bodies. They were frequently associated not only with alpha-synuclein-positive Lewy neurites, but also with TH-16-positive dopaminergic and WH-3-positive serotonergic neurites, as well as MAP-2- and SMI-32-positive neurites. These activated microglia were also positive for TNF-alpha and interleukin-6, which are known to have a neuroprotective function. We conclude that MHC class II-positive microglia are a sensitive index of neuropathological change and are actively associated with damaged neurons and neurites.
Tyrosine hydroxylase (TH), which catalyzes the conversion of l-tyrosine to l-DOPA, is the rate-limiting enzyme in the biosynthesis of catecholamines. It is well known that both α-synuclein and 14-3-3 ...protein family members bind to the TH molecule and regulate phosphorylation of its N-terminus by kinases to control the catalytic activity. In this present study we investigated whether other proteins aside from these 2 proteins might also bind to TH molecules. Nano-LC-MS/MS analysis revealed that 5′-nucleotidase domain-containing protein 2 (NT5DC2), belonging to a family of haloacid dehalogenase-type (HAD) phosphatases, was detected in the immunoprecipitate of PC12D cell lysates that had been reacted with Dynabeads protein G-anti-TH antibody conjugate. Surprisingly, NT5DC2 had already been revealed by Genome-Wide Association Studies (GWAS) as a gene implicated in neuropsychiatric disorders such as schizophrenia, bipolar disorder, which are diseases related to the abnormality of dopamine activity in the brain, although the role that NT5DC2 plays in these diseases remains unknown. Therefore, we investigated the effect of NT5DC2 on the TH molecule. The down-regulation of NT5DC2 by siRNA increased the synthesis of catecholamines (dopamine, noradrenaline, and adrenaline) in PC12D cells. These increases might be attributed to the catalytic activity of TH and not to the intracellular stability of TH, because the intracellular content of TH assessed by Western blotting was not changed by the down-regulation of NT5DC2. Collectively, our results indicate that NT5DC2 inhibited the synthesis of dopamine by decreasing the enzymatic activity of TH.
•Nano-LC-MS/MS revealed that NT5DC2 binds to tyrosine hydroxylase in PC12D cells.•Down-regulation of NT5DC2 by siRNA increased the synthesis of catecholamines.•NT5DC2 had already been revealed as a gene implicated in neuropsychiatric disorders.
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