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1.
Mitochondria and Neurodegeneration 总被引:2,自引:0,他引:2
Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration. 相似文献
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Electron paramagnetic resonance spectroscopy (EPR) has the potential to give much detail on the structure of the paramagnetic
transition ion coordination sites, principally of Cu2+, in a number of proteins associated with central nervous system diseases. Since these sites have been implicated in misfolding/mis-oligomerisation
events associated with neurotoxic molecular species and/or the catalysis of damaging redox reactions in neurodegeneration,
an understanding of their structure is important to the development of therapeutic agents. Nevertheless EPR, by its nature
an in vitro technique, has its limitations in the study of such complex biochemical systems involving self-associating proteins
that are sensitive to their chemical environment. These limitations are at the instrumental and theoretical level, which must
be understood and the EPR data interpreted in the light of other biophysical and biochemical studies if useful conclusions
are to be drawn.
Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience, held in Melbourne on 11 July 2007. 相似文献
4.
Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review
we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides
CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix.
The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the
one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of
electron transfer to the acceptor, CoQ. Complex I is deeply involved in pathological changes, including neurodegeneration.
Complex I changes are involved in common neurological diseases of the adult and old ages. Mitochondrial cytopathies due to
mutations of either nuclear or mitochondrial DNA may represent a useful model of neurodegeneration. In this review we discuss
Parkinson’s disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode
of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and
pathogenesis of the disease.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
5.
Hui KS 《Neurochemical research》2007,32(12):2062-2071
The major breakthrough discovery of enkephalins as endogenous opiates led our attempts to determine their inactivation mechanisms.
Because the NH2-terminal tyrosine is absolutely necessary for the neuropeptides to exert analgesic effects, and aminopeptidase
activities are extraordinarily high in the brain, a specific “amino-enkephalinase” should exist. Several aminopeptidases were
identified in the central nervous system during the search. In fact, our laboratory found two novel neuron-specific aminopeptidases:
NAP and NAP-2. NAP is the only functionally active brain-specific enzyme known. Its synaptic location coupled with its limited
substrate specificity could constitute a “functional” specificity and contribute to enkephalin-specific functions. In addition,
NAP was found to be essential for neuron growth, differentiation, and death. Thus, aminopeptidases are likely important for
mental health and neurological diseases. Recently, puromycin-sensitive aminopeptidase (PSA) was identified as a modifier of
tau-induced neurodegeneration. Because the enzymatic similarity between PSA and NAP, we believe that the depletion of NAP
in Alzheimer’s disease (AD) brains plays a causal role in the development of AD pathology. Therefore, use of the puromycin-sensitive
neuron-aminopeptidase NAP could provide neuroprotective mechanisms in AD and similar neurodegenerative diseases.
Special issue in honor of Naren Banik. 相似文献
6.
The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease
afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of
the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies
that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of
some of the most devastating diseases of old age. 相似文献
7.
Gaasch JA Geldenhuys WJ Lockman PR Allen DD Van der Schyf CJ 《Neurochemical research》2007,32(10):1686-1693
Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC
may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative
diseases such as Parkinson’s and Alzheimer’s disease. VGCCs, ubiquitously expressed, may be an important route of excessive
entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of 45Ca2+ and 55Fe2+ into NGF-treated rat PC12, and murine N-2α cells. Iron not only competed with calcium for entry into these cells, but iron
uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176,
an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are
an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
8.
Uberti D Bianchi I Olivari L Ferrari-Toninelli G Bonini SA Memo M 《Neurochemical research》2007,32(10):1726-1729
Dopaminergic agonists have been usually used as adjunctive therapy for the cure of Parkinson’s disease (PD). It is generally
believed that treatment with these drugs is symptomatic rather then curative and does not stop or delay the progression of
neuronal degeneration. However, several DA agonists of the DA D2–receptor family (including D2, D3 and D4-subtypes) have recently
been shown to possess neuroprotective properties in different in vitro and in vivo experimental PD models. Here we summarize
some recent data from our and other groups underlining the wide pharmacological spectrum of DA agonists currently used for
treating PD patients. In particular, the mechanism of action of different DA agonists does not appear to be restricted to
the stimulation of selective DA receptor subtypes being these drugs endowed with intrinsic, independent, and peculiar antioxidant
effects. This activity may represent an additional pharmacological property contributing to their clinical efficacy in PD.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
9.
The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective
was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors
in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most
frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral
amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four
degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide
dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD,
HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF
and appeared to be a good biomarker of PD. 相似文献
10.
Yoshida T Mizuta T Shimizu S 《Biochemical and biophysical research communications》2010,402(4):676-679
Parkinson’s disease (PD) is a common neurodegenerative disorder. The motor neuron degeneration 2 mutant (mnd2) mouse is considered to be an animal model of PD, and exhibits striatal neuron loss, severe muscle wasting, weight loss and death before 40 days of age. We found for the first time that parkin expression was decreased in the mnd2 mouse brain. Since parkin is a crucial protein for PD, the neurodegenerative disorder in mnd2 mice may be caused by parkin protein loss. We therefore examined whether compensation of parkin protein prevents neurodegenerative disorders in mnd2 mice by generating parkin-transgenic (parkin-Tg) mnd2 mice. However, both parkin-Tg mnd2 mice and mnd2 mice were smaller than wild type mice. In muscle strength and survival rate, parkin-Tg mnd2 mice showed similar values to mnd2 mice. Our data suggest that repression of parkin protein does not play a major role in neurodegeneration of mnd2 mice and administration of parkin protein does not rescue mnd2 mice. 相似文献
11.
Gdynia G Lehmann-Koch J Sieber S Tagscherer KE Fassl A Zentgraf H Matsuzawa S Reed JC Roth W 《Apoptosis : an international journal on programmed cell death》2008,13(3):437-447
The HIPPI (HIP-1 protein interactor) protein is a multifunctional protein that is involved in the regulation of apoptosis.
The interaction partners of HIPPI include HIP-1 (Huntingtin-interacting protein-1), Apoptin, Homer1c, Rybp/DEDAF, and BAR
(bifunctional apoptosis regulator). In search for other binding partners of HIPPI, we performed a yeast two hybrid screen
and identified BLOC1S2 (Biogenesis of lysosome-related organelles complex-1 subunit 2) as a novel HIPPI-interacting protein.
In co-immunoprecipitation assays, BLOC1S2 specifically associates with HIPPI, but not with HIP-1. To study the expression
of BLOC1S2 on the protein level, we generated a mouse monoclonal antibody specific for BLOC1S2 and a multiple tissue array
comprising 70 normal and cancer tissue samples of diverse origin. BLOC1S2 protein is widely expressed in normal tissue as
well as in malignant tumors with a tendency towards lower expression levels in certain subtypes of tumors. On the subcellular
level, BLOC1S2 is expressed in an organellar-like pattern and co-localizes with mitochondria. Over-expression of BLOC1S2 in
the presence or absence of HIPPI does not induce apoptosis. However, BLOC1S2 and HIPPI sensitize NCH89 glioblastoma cells
to the pro-apoptotic actions of staurosporine and the death ligand TRAIL by enhancing caspase activation, cytochrome c release,
and disruption of the mitochondrial membrane potential. Given its interaction with HIPPI and its pro-apoptotic activity, BLOC1S2
might play an important functional role in cancer and neurodegenerative diseases. 相似文献
12.
Hyperphosphorylation and aggregation of tau into tangles is a feature of disorders such as Alzheimer’s disease and other Tauopathies.
To model these disorders in Drosophila melanogaster, human tau has been over-expressed and a variety of phenotypes have been observed including neurotoxicity, disrupted neuronal
and synaptic function and locomotor impairments. Neuronal dysfunction has been seen prior to neuronal death and in the absence
of tangle formation. The Drosophila tau protein shares a large degree of homology with human tau but differs in the crucial microtubule binding domains. Although
like human tau Drosophila tau can induce neurotoxicity, little is known about its ability to disrupt neuronal function. In this study we demonstrate
that like human tau, over-expression of Drosophila tau results in disrupted axonal transport, altered neuromuscular junction morphology and locomotor impairments. This indicates
that like human tau, over-expression of Drosophila tau compromises neuronal function despite significant differences in microtubule binding regions. 相似文献
13.
Schapira AH 《Neurochemical research》2008,33(12):2502-2509
Mitochondria play a pivotal role in mammalian cell metabolism, hosting a number of important biochemical pathways including
oxidative phosphorylation. As might be expected from this fundamental contribution to cell function, abnormalities of mitochondrial
metabolism are a common cause of human disease. Primary mutations of mitochondrial DNA result in a diverse group of disorders
often collectively referred to as the mitochondrial encephalomyopathies. Perhaps more importantly in numerical terms are those
neurodegenerative diseases caused by mutations of nuclear genes encoding mitochondrial proteins. Finally there are mitochondrial
abnormalities induced by secondary events e.g. oxidative stress that may contribute to senescence, and environmental toxins
that may cause disease either alone or in combination with a genetic predisposition.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
14.
Several lines of evidence support the neuroprotective action of cyclooxygenase-2 (COX-2) inhibitors in various models of Parkinson’s
disease (PD). In the current study, we investigated the neuroprotective properties of several COX inhibitors against 1-methyl-4-phenylpyridinium
(MPP+) in neuroblastoma Neuro 2A (N-2A) cells in vitro and the protection against degeneration of substantia nigra pars compacta
(SNc) dopaminergic (DA) neurons after the administration of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) in C57/BL6
male mice. The data obtained demonstrate a lack of protective effects observed by COX 1-2 inhibitors ibuprofen and acetylsalicylic
acid against MPP+ toxicity in N-2A, where piroxicam was protective in a dose dependent manner (MPP+ control: 15 ± 2% MPP+
piroxicam: 5 mM 89 ± 4%). The data also indicate a drop in mitochondrial oxygen (O2) consumption and ATP during MPP+ toxicity with no restoration of mitochondrial function concurrent to a heightened concentration
of somatic ATP during piroxicam rescue. These findings indicate that the neuroprotective effects of COX inhibitors against
MPP+ are not consistent, but that piroxicam may work through an unique mechanism to propel anaerobic energy metabolism. On
the other hand, using mice, piroxicam (20 mg/kg) was effective against MPTP-induced dopaminergic degeneration in the (SNc)
and loss of locomotive function in mice. Administering a 3 day pre-treatment of piroxicam (20 mg/kg) was effective in antagonizing
the losses in SNc tyrosine hydroxylase protein expression, SNc DA concentration and associated anomaly in ambulatory locomotor
activity. It was concluded from these findings that piroxicam is unique among COX inhibitors in providing very significant
neuroprotection against MPP+ in vitro and in vivo. 相似文献
15.
Baolu Zhao 《Neurochemical research》2009,34(4):630-638
“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams
very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the
immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs
not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they
usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s
disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many
targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews
the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized
the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models,
and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models.
Special issue in honor of Dr. Akitane Mori. 相似文献
16.
Caricasole A Bakker A Copani A Nicoletti F Gaviraghi G Terstappen GC 《Bioscience reports》2005,25(5-6):309-327
Wnts function through the activation of at least three intracellular signal transduction pathways, of which the canonical
β-catenin mediated pathway is the best understood. Aberrant canonical Wnt signaling has been involved in both neurodegeneration
and cancer. An impairment of Wnt signals appears to be associated with aspects of neurodegenerative pathologies while overactivation
of Wnt signaling is a common theme in several types of human tumors. Therefore, although therapeutic approaches aimed at modulating
Wnt signaling in neurodegenerative and hyperproliferative diseases might impinge on the same molecular mechanisms, different
pharmacological outcomes are required. Here we review recent developments on the understanding of the role of Wnt signaling
in Alzheimer’s disease and CNS tumors, and identify possible avenues for therapeutic intervention within a complex and multi-faceted
signaling pathway. 相似文献
17.
Majumder P Raychaudhuri S Chattopadhyay B Bhattacharyya NP 《Cellular and molecular neurobiology》2007,27(8):1127-1145
(1) Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of polymorphic CAG
repeats beyond 36 at exon 1 of huntingtin gene (htt). To study cellular effects by expressing N-terminal domain of Huntingtin (Htt) in specific cell lines, we expressed exon
1 of htt that codes for 40 glutamines (40Q) and 16Q in Neuro2A and HeLa cells. (2) Aggregates and various apoptotic markers were detected
at various time points after transfection. In addition, we checked the alterations of expressions of few apoptotic genes by
RT-PCR. (3) Cells expressing exon 1 of htt coding 40Q at a stretch exhibited nuclear and cytoplasmic aggregates, increased caspase-1, caspase-2, caspase-8, caspase-9/6,
and calpain activations, release of cytochrome c and AIF from mitochondria in a time-dependent manner. Truncation of Bid was increased, while the activity of mitochondrial
complex II was decreased in such cells. These changes were significantly higher in cells expressing N-terminal Htt with 40Q
than that obtained in cells expressing N-terminal Htt with 16Q. Expressions of caspase-1, caspase-2, caspase-3, caspase-7,
and caspase-8 were increased while expression of Bcl-2 was decreased in cells expressing mutated Htt-exon 1. (4) Results presented
in this communication showed that expression of mutated Htt-exon 1 could mimic the cellular phenotypes observed in Huntington’s
disease and this cell model can be used for screening the agents that would interfere with the apoptotic pathway and aggregate
formation. 相似文献
18.
《Journal of trace elements in medicine and biology》2014,28(4):418-421
Osteoporosis affects bone microarchitecture and reduces bone mass. There are more than 200 million people with osteoporosis worldwide, and the prevalence is slowly increasing. The highest prevalences are found in Scandinavia and USA, also slowly increasing. A parallel increase in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis has been noted since the middle of this century. Osteoporosis is more common in patients with each of these neurodegenerative conditions than in the general population. Several metals with neurotoxic properties accumulate in bone and can substitute for calcium in hydroxyapatite, the main mineral component of bone. Especially cadmium, but also lead, aluminum and arsenic affect bone mineral density negatively. Metals with neurotoxic properties have also been found in brain and cerebrospinal fluid from patients with Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis, and markers for neurodegeneration such as amyloid beta peptide and amyloid precursor protein have been detected in bone tissue from patients with osteoporosis. A common mechanism contributing to the pathogenesis of both neurodegeneration and osteoporosis can be suspected. The hypothesis that neurodegenerative disorders are associated with osteoporosis is presented and discussed. 相似文献
19.
Ren M. Q. Thong P. S. P. Makjanic J. Ponraj D. Watt F. 《Biological trace element research》1999,(1):65-76
The nuclear microscope is now gaining popularity in the field of life sciences. In particular, the combination of proton-induced
X-ray emission to measure the elemental concentrations of inorganic elements, Rutherford backscattering spectrometry to characterize
the organic matrix, and scanning transmission ion microscopy to provide information on the density and structure of the sample
represents a powerful set of techniques that can be applied simultaneously to the specimen under investigation. These techniques
are extremely useful for measuring any imbalances in trace elements in localized regions of biological tissue and, as such,
can provide unique information on many diseases. In this article, we describe the nuclear microscope and its related ionbeam
techniques, and we review the biomedical work carried out using the nuclear microscope in the National University of Singapore. 相似文献