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1.
α-Synuclein and dopamine metabolism 总被引:4,自引:0,他引:4
α-Synuclein (α-Syn), a 140-amino-acid protein richly expressed in presynaptic terminals in the central nervous system, has
been shown to play a central role in the pathogenesis of Parkinson’s disease. Although the normal functions of α-Syn remain
elusive, accumulating evidence shows that the molecule is involved in multiple steps related to dopamine metabolism, including
dopamine synthesis, storage, release, and uptake. The regulatory effect of α-Syn on dopamine metabolism is likely to tone
down the amount of cytoplasmic dopamine at nerve terminals, thereby limiting its conversion to highly reactive oxidative molecules.
Formation of α-Syn protofibrils triggered by factors such as gene mutations and environmental toxins can make the molecule
lose its normal functions, leading to disrupted homeostasis of dopamine metabolism, increased cytoplasmic dopamine levels,
and enhanced oxidative stress in dopaminergic neurons. The enhanced oxidative stress will, in turn, exacerbate the formation
of α-Syn protofibrils and drive the neurons into a vicious cycle, which will finally result in the selective degeneration
of the dopaminergic neurons associated with Parkinson’s disease. 相似文献
2.
3.
Salsolinol, an endogenous neurotoxin, is known to be involved in the pathogenesis of Parkinson’s disease (PD). In the present
study, we have investigated the effects of salsolinol on the activation of two different signaling pathways that involve c-Jun
N-terminal kinase (JNK), and nuclear factor-κB, (NF-κB) in human dopaminergic neuroblastoma SH-SY5Y cells. Salsolinol treatment
caused upregulation in the levels of c-Jun and phosphorylated c-Jun. It also caused degradation of IκBα and translocated the
active NF-κB into the nucleus. The binding activity of NF-κB to DNA was enhanced by salsolinol in a concentration dependent
manner. Furthermore, salsolinol decreased the levels of the anti-apoptotic protein Bcl-2, and increased pro-apoptotic protein
Bax, while enhancing the release of cytochrome-c from mitochondria. Mitochondrial complex-I activity was significantly decreased and reactive oxygen species (ROS) were increased
in salsolinol treated cells. These results partly suggest that salsolinol-induced JNK and NF-κB signaling pathways may be
involved in induction of apoptosis in human dopaminergic neurons, as seen in Parkinson’s disease. 相似文献
4.
One of the strategies of treating Parkinson’s disease (PD) is the replacement of lost neurons in the substantia nigra with
healthy dapamingergic cells. Potential sources for cells range from autologous grafts of dopamine secreting cells, fetal ventral
mesencephalon tissue, to various stem cell types. Over the past quarter century, many experimental replacement therapies have
been tried on PD animal models as well as human patients, yet none resulted in satisfactory outcomes that warrant wide applications.
Recent progress in stem cell biology has shown that nuclear transfer embryonic stem cells (ntES) or induced pluripotent stem
cells (iPS) derived cells can be used to successfully treat rodent PD models, thus solving the problem of immunorejection
and paving the way for future autologous transplantations for treating PD. Meanwhile, however, post mortem analysis of patients
who received fetal brain cell transplantation revealed that implanted cells are prone to degeneration just like endogenous
neurons in the same pathological area, indicating long-term efficacy of cell therapy of PD needs to overcome the degenerating
environment in the brain. A better understanding of neurodegeneration in the midbrain appeared to be a necessary step in developing
new cell therapies in Parkinson’s disease. It is likely that future cell replacement will focus on not only ameliorating symptoms
of the disease but also trying to slow the progression of the disease by either neuroprotection or restoring the micro-environment
in the midbrain.
Support by the National Key Basic Research and Development Program of China (Grant No. 2006CB0F0603) and Science and Technology
Plan, Beijing Municipal Science & Technology Commission (Grant No. H020220010290) 相似文献
5.
We explore the behavior of richly connected inhibitory neural networks under parameter changes that correspond to weakening
of synaptic efficacies between network units, and show that transitions from irregular to periodic dynamics are common in
such systems. The weakening of these connections leads to a reduction in the number of units that effectively drive the dynamics
and thus to simpler behavior. We hypothesize that the multiple interconnecting loops of the brain’s motor circuitry, which
involve many inhibitory connections, exhibit such transitions. Normal physiological tremor is irregular while other forms
of tremor show more regular oscillations. Tremor in Parkinson’s disease, for example, stems from weakened synaptic efficacies
of dopaminergic neurons in the nigro-striatal pathway, as in our general model. The multiplicity of structures involved in
the production of symptoms in Parkinson’s disease and the reversibility of symptoms by pharmacological and surgical manipulation
of connection parameters suggest that such a neural network model is appropriate. Furthermore, fixed points that can occur
in the network models are suggestive of akinesia in Parkinson’s disease. This model is consistent with the view that normal
physiological systems can be regulated by robust and richly connected feedback networks with complex dynamics, and that loss
of complexity in the feedback structure due to disease leads to more orderly behavior. 相似文献
6.
7.
Recent findings indicate that VTA and SN dopaminergic (DA) and GABAergic neurons form subpopulations that are divergent in
their electrophysiological features, vulnerability to neurodegeneration, and regulation by neuropeptides. This diversity can
be correlated with the anatomical organization of the VTA and SN and their inputs and outputs. In this review we describe
the heterogeneity in ion channels and firing patterns, especially burst firing, in subpopulations of dopamine neurons. We
go on to describe variations in vulnerability to neurotoxic damage in models of Parkinson’s disease in subgroups of DA neurons
and its possible relationship to developmental gene regulation, the expression of different ion channels, and the expression
of different protein markers, such as the neuroprotective marker calbindin. The electrophysiological properties of subgroups
of GABAergic midbrain neurons, patterns of expression of protein markers and receptors, possible involvement of GABAergic
neurons in a number of processes that are usually attributed exclusively to dopaminergic neurons, and the characteristics
of a subgroup of neurons that contains both dopamine and GABA are also discussed. 相似文献
8.
α-Synuclein plays a key role in the pathological neurodegeneration in Parkinson’s disease. Although its contribution to normal
physiology remains elusive, the selective degeneration of α-synuclein-containing dopaminergic neurons in Parkinson’s disease
may be linked to abnormal α-synuclein induced toxicity. In the present study, a complex of α-synuclein and vesicular monoamine
transporter-2 was identified by GST-Pull Down experiment. In wild-type α-synuclein stably transfected SH-SY5Y cell lines,
the activity of vesicular monoamine transporter-2 decreased by 31% as determined by [3H] dopamine uptake, and its expression also decreased in both protein and mRNA levels using western and northern blot analysis.
Overexpression of wild-type α-synuclein did not induce cell death or apoptosis, but significantly enhanced the intracellular
reactive oxygen species level as assayed by flow cytometry. These data suggest that Up-regulated α-synuclein expression inhibits
the activity of vesicular monoamine transporter-2, thereby interrupting dopamine homeostasis and resulting in dopaminergic
neuron injury in Parkinson’s disease. 相似文献
9.
Wang Xiao-Le Feng Si-Tong Wang Ya-Ting Yuan Yu-He Li Zhi-Peng Chen Nai-Hong Wang Zhen-Zhen Zhang Yi 《Cellular and molecular neurobiology》2022,42(5):1321-1339
Cellular and Molecular Neurobiology - Parkinson’s disease (PD) is a severe neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra and... 相似文献
10.
11.
Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia
possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus,
and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The
experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with
simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility
during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects.
In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration
of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It
was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or
stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor
of adenosine A2A receptors, as an anti-Parkinson drug. 相似文献
12.
The role of the interaction between neurons and glial cells in the pathogenesis of neurodegenerative diseases is gaining more
attention. Neuroinflammation participates in the progressive nature of diverse neurologic diseases including Parkinson's disease,
Alzheimer's disease and multiple sclerosis. Activated microglia release neurotoxic molecules, which take part in the neuroinflammatory
responses. Astrocytes are also key players in these responses. Reactive astrocytes secrete inflammatory factors, including
tumor necrosis factor-α (TNF-α). This secretion can be regulated by extracellular ATP mediated through P2X7 receptors. However,
whether the activity of astrocytic P2X7 receptors changes in Parkinson’s disease and whether these changes would influence
the secretion of inflammatory factors in astrocytes are still unclear. In our study, through immunocytochemistry, whole-cell
patch clamp and ELISA assay, we found that P2X7 receptors were expressed in midbrain astrocytes, and that, rotenone, a Parkinson’s
disease model used at a low concentration (2–20 nM) for 48 h increased the P2X7 receptor current density and thereby inhibited
the secretion of TNF-α. Our research suggests that rotenone can regulate cytokine secretion of astrocytes through elevated
P2X7 channel current density and, in turn, take part in the neuroinflammatory process in the rotenone Parkinson’s disease
model. 相似文献
13.
Parkinson’s disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson’s disease is discussed in this review. 相似文献
14.
In Alzheimer and Parkinson’s disease cell death of cholinergic and dopaminergic neurons are characteristic hallmarks, respectively.
It is well established that rotenone, an inhibitor of complex I of the electron transport chain, induces cell death of dopaminergic
neurons, however, not much is known on the effects of rotenone on cholinergic neurons. The aim of the present study was to
evaluate the effects of rotenone on cholinergic neurons in an organotypic in vitro brain co-slice model. When co-cultures
were treated with 10 μM rotenone for 24 h a significantly decreased number of cholinergic neurons was found in the basal nucleus
of Meynert but not in the dorsal striatum. This cell death exhibited apoptotic DAPI-positive malformed nuclei and enhanced
TUNEL-positive cells. In summary, inhibition of complex I of the electron transport chain may play a role in neurodegeneration
of cholinergic neurons. 相似文献
15.
Saeed Esmaeili-Mahani Somayeh Vazifekhah Hamzeh Pasban-Aliabadi Mehdi Abbasnejad Vahid Sheibani 《Neurochemistry international》2013
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by progressive and selective death of midbrain dopaminergic neurons. Pharmacologic treatment of PD can be divided into symptomatic and neuroprotective therapies. 相似文献
16.
Dopamine (DA) and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily
due to the generation of highly reactive DA and DOPA quinones. Quinone formation is closely linked to other representative
hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome
system, in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease and methamphetamine-induced neurotoxicity.
Therefore, pathogenic effects of the DA quinone have focused on dopaminergic neuron-specific oxidative stress. Recently, various
studies have demonstrated that some intrinsic molecules and several drugs exert protective effects against DA quinone-induced
damage of dopaminergic neurons. In this article, we review recent studies on some neuroprotective approaches against DA quinone-induced
dysfunction and/or degeneration of dopaminergic neurons.
Special issue article in honor of Dr. Akitane Mori. 相似文献
17.
18.
Stem cells and neurodegenerative diseases 总被引:1,自引:0,他引:1
Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease. 相似文献
19.
Mathieu Marella Byoung Boo Seo Takao Yagi Akemi Matsuno-Yagi 《Journal of bioenergetics and biomembranes》2009,41(6):493-497
Mitochondrial impairment has been collecting more and more attention as a contributing factor to the etiology of Parkinson’s
disease. Above all, the NADH-quinone oxidoreductase, complex I, of the respiratory chain seems to be most culpable. Complex
I dysfunction is translated to an increased production of reactive oxygen species and a decreased energy supply. In the brain,
the dopaminergic neurons are one of the most susceptible cells. Their death is directly linked to the disease apparition.
Developing an effective gene therapy is challenged by harmful actions of reactive oxygen species. To overcome this problem
a therapeutic candidate must be able to restore the NADH-quinone oxidoreductase activity regardless of how complex I is impaired.
Here we discuss the potency of the yeast alternative NADH dehydrogenase, the Ndi1 protein, to reinstate the mitochondrial
respiratory chain compensating for disabled complex I and the benefit Ndi1 brings toward retardation of Parkinson’s disease. 相似文献
20.
Tyrosine kinase receptors TrkB and TrkC mediate neuroprotective effects of the brain-derived neurotrophic factor (BDNF) and
neurotrophins in the dopaminergic nigro-striatal system, but it is obscure about their responses or expression changes in
the injured substantia nigra under Parkinson’s disease. In present study, immunofluorescence, Fluoro-Jade staining and laser
scanning confocal microscopy were applied to investigate distribution and changes of TrkB and TrkC in the dopamine neurons
of the substantia nigra by comparison of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. It revealed
that TrkB and TrkC-immunoreactivities were substantially localized in cytoplasm and cell membrane of the substantia nigra
neurons of control adults. While neurons double-labeled with tyrosine hydroxylase (TH)/TrkB, or TH/TrkC were distributed in
a large numbers in the substantia nigra of controls, they apparently went down at 36.2–65.7% of normal level, respectively
following MPTP insult. In MPTP model, cell apoptosis or degeneration of nigral neurons were confirmed by caspase-3 and Fluoro-Jade
staining. More interestingly, TH/TrkB-positive neurons survived more in cell numbers in comparison with that of TH/TrkC-positive
ones in the MPTP model. This study has indicated that TrkB-containing dopamine neurons are less sensitive in the substantia
nigra of MPTP mouse model, suggesting that specific organization of Trks may be involved in neuronal vulnerability to MPTP
insult, and BDNF-TrkB signaling may play more important role in protecting dopamine neurons and exhibit therapeutic potential
for Parkinson’s disease. 相似文献