Journal of Neural Transmission-supplement最新文献

In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.

Friedreich ataxia is due to insufficient levels of frataxin, a mitochondrial iron chaperone that shields this metal from reactive oxygen species (ROS) and renders it bioavailable as Fe II. Frataxin participates in the synthesis of iron-sulfur clusters (ISCs), cofactors of several enzymes, including mitochondrial and cytosolic aconitase, complexes I, II and III of the respiratory chain, and ferrochelatase. It also plays a role in the maintenance of ISCs, in particular for mitochondrial aconitase. A role of frataxin in heme synthesis has been postulated, but is controversial. Insufficient frataxin leads to deficit of ISC enzymes and energy deficit. Iron levels increase in mitochondria. Oxidative stress may result from respiratory chain dysfunction and from direct reaction between iron and ROS. Stress pathways are activated that may lead to apoptosis or other forms of cell death. The basis for the selective vulnerability of specific neurons, like sensory neurons, is still unknown.

The long-term effects of rehabilitated infancy (1 year old) iron deficiency (ID) were examined at age 10. The children were examined for the following variables: auditory system function, the level of morning cortisol, I.Q. score (WISC-R), and behavioral profile. The results indicate that while the former ID children's hearing system appears to function well, there was a delay in brain stem processing of the auditory signals. In addition, the level of morning cortisol was reduced, the general I.Q. scores were lower than the normal group (mainly in the performed subtest), and more sleep disturbances and fatigue during day were reported. These outcomes are consistent with established reports on the effect of iron deficiency on the rate of myelination in selected brain areas during critical period of 1 year olds. The findings of increased sleep disturbances and lower I.Q. tests require further study.

Glial cell line-derived neurotrophic factor (GDNF) has been known for many years to protect and restore dopamine neurons of the substantia nigra (SN) in lesion models of parkinsonism, but much less has been known of its normal physiologic role. We have found that GDNF injected into the striatum postnatally suppresses naturally-occurring cell death in SN dopamine neurons, and neutralizing antibodies augments it. Neutralizing antibodies augment cell death during the first phase, which occurs during the first postnatal week, but not during the second phase in the second week. To further explore the possible neurotrophic role of GDNF, we created double transgenic mice which overexpress GDNF exclusively in the target regions of mesencephalic neurons, particularly the striatum. As anticipated for a limiting, target-derived factor, this resulted in an increased surviving number of SN dopamine neurons after the first phase of cell death. However, this increase did not persist into adulthood. We conclude that GDNF is the leading candidate for a target-derived neurotrophic factor for SN dopamine neurons during the first phase of cell death, but that other factors must play an essential role in later development.

Dopamine belongs to the most intensively studied neurotransmitters of the brain, because of its implications in psychiatric and neurological disorders. Although, clinical relevance of midbrain dopaminergic (mDA) neurons is well recognized and dopaminergic dysfunction may have a genetic component, the genetic cascades underlying developmental processes are still largely unknown. With the advances in molecular biology, mDA neurons and their involvement in psychiatric and neurological disorders are now subject of studies that aim to delineate the fundamental neurobiology of these neurons. These studies are concerned with developmental processes, cell-specific gene expression and regulation, molecular pharmacology, and genetic association of dopamine-related genes and mDA-associated disorders. Several transcription factors implicated in the post-mitotic mDA development, including Nurr1, Lmx1b, Pitx3, and En1/En2 have contributed to the understanding of how mDA neurons are generated in vivo. Furthermore, these studies provide insights into new strategies for future therapies of Parkinson's Disease (PD) using stem cells for engineering DA neurons in vitro. Here, we will discuss the role of Pitx3 in molecular mechanisms involved in the regional specification, neuronal specification and differentiation of mDA neurons.

In the traditional model of the pathophysiology of parkinsonism, parkinsonian motor signs are viewed as the result of changes in discharge rates in the basal ganglia. However, not all experimental findings can be explained by rate changes alone, and changes in discharge patterns in these nuclei are increasingly emphasized as pathophysiologically important, including changes in burst discharges, in synchrony, and in oscillatory activity. This brief review highlights the pathophysiologic relevance of these rate and pattern changes in the pathophysiology of parkinsonism.

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronise their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronised oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and movement suppress this activity, with the timing and degree of suppression closely correlating with behavioural performance. Accordingly synchronisation in the beta band has been hypothesised to be essentially antikinetic in nature and pathophysiologically relevant to bradykinesia.

Studying potential neuroprotective therapy for Parkinson's disease is conceptually problematic because of the heterogenous nature of the Parkinson's syndrome and complexities in operational definitions for neuroprotection. The current literature concerning neuroprotection provides no convincing evidence of any treatment as definitively neuroprotective in Parkinson's disease. Recent clinical trials and novel trial designs are reviewed that may identify meaningful therapy, resulting in maintenance of neurological function and quality of life for persons with Parkinson's disease.

Owing to its ability to undergo one-electron reactions, iron transforms the mild oxidant hydrogen peroxide into hydroxyl radical, one of the most reactive species in nature. Deleterious effects of iron accumulation are dramatically evidenced in several neurodegenerative diseases. The work of Youdim and collaborators has been fundamental in describing the accumulation of iron confined to the substantia nigra (SN) in Parkinson's disease (PD) and to clarify iron toxicity pathways and oxidative damage in dopaminergic neurons. Nevertheless, how the mechanisms involved in normal neuronal iron homeostasis are surpassed, remain largely undetermined. How nigral neurons survive or succumb to iron-induced oxidative stress are relevant questions both to know about the etiology of the disease and to design neuroprotective strategies. In this work, we review the components of neural iron homeostasis and we summarize evidence from recent studies aimed to unravel the molecular basis of iron accumulation and dyshomeostasis in PD.

Iron closely regulates the expression of the Alzheimer's Amyloid Precursor Protein (APP) gene at the level of message translation by a pathway similar to iron control of the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5' untranslated regions (5'UTRs). Using transfection based assays in SH-SY5Y neuroblastoma cells we tested the relative efficiency by which iron, copper and zinc up-regulate IRE activity in the APP 5'UTR. Desferrioxamine (high affinity Fe3+ chelator), (ii) clioquinol (low affinity Fe/Cu/Zn chelator), (iii) piperazine-1 (oral Fe chelator), (iv) VK-28 (oral Fe chelator), were tested for their relative modulation of APP 5' UTR directed translation of a luciferase reporter gene. Iron chelation based therapeutic strategies for slowing the progression of Alzheimer's disease (and other neurological disorders that manifest iron imbalance) are discussed with regard to the relative neural toxic action of each chelator in SH-SY5Y cells and in H4 glioblastoma cells.