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Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced mouse model of Parkinson's disease 下载免费PDF全文
Aine Tonouchi Jun Nagai Kentaro Togashi Yoshio Goshima Toshio Ohshima 《Journal of neurochemistry》2016,137(5):795-805
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Nasrollah Rezaei‐Ghaleh Nora Wender Hai‐Young Kim Grit Taschenberger Björn H Falkenburger Henrike Heise Ashutosh Kumar Dietmar Riedel Lars Fichtner Aaron Voigt Gerhard H Braus Karin Giller Stefan Becker Alf Herzig Marc Baldus Herbert Jäckle Stefan Eimer Jörg B Schulz Christian Griesinger Markus Zweckstetter 《The EMBO journal》2009,28(20):3256-3268
The relation of α‐synuclein (αS) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated αS species have in neurotoxicity in vivo, we generated αS variants by a structure‐based rational design. Biophysical analysis revealed that the αS mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre‐fibrillar αS mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between αS aggregates with impaired β‐structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric αS species and their in vivo function. 相似文献
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Aritri Bir Oishimaya Sen Shruti Anand Vineet Kumar Khemka Priyanjalee Banerjee Roberto Cappai Arghyadip Sahoo Sasanka Chakrabarti 《Journal of neurochemistry》2014,131(6):868-877
This study has shown that purified recombinant human α‐synuclein (20 μM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 μM), a proteasomal inhibitor, causes an accumulation of α‐synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down α‐synuclein expression by specific siRNA. Furthermore, in wild‐type (non‐transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 μM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild‐type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 μM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated α‐synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.
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Jun Liu Min Shi Zhen Hong JianPeng Zhang Joshua Bradner Thomas Quinn Richard P. Beyer Patrick L. Mcgeer ShengDi Chen Jing Zhang 《Proteomics》2010,10(11):2138-2150
Accumulating evidence suggests that extracellular α‐synuclein (eSNCA) plays an important role in the pathogenesis of Parkinson's disease or related synucleinopathies by inducing neurotoxicity directly or indirectly via microglial or astroglial activation. However, the mechanisms by which this occurs remain to be characterized. To explore these mechanisms, we combined three biochemical techniques – stable isotope labeling of amino acid in cell cultures (SILAC), biotin labeling of plasma membrane proteins followed by affinity purification, and analysis of unique proteins binding to SNCA peptides on membrane arrays. The SILAC proteomic analysis identified 457 proteins, of which, 245 or 172 proteins belonged to membrane or membrane associated proteins, depending on the various bioinformatics tools used for interpretation. In dopamine neuronal cells treated with eSNCA, the levels of 86 membrane proteins were increased and 35 were decreased compared with untreated cells. In peptide array analysis, 127 proteins were identified as possibly interacting with eSNCA. Of those, seven proteins were overlapped with the membrane proteins that displayed alterations in relative abundance after eSNCA treatment. One was ciliary neurotrophic factor receptor, which appeared to modulate eSNCA‐mediated neurotoxicity via mechanisms related to JAK1/STAT3 signaling but independent of eSNCA endocytosis. 相似文献
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Sabrina Büttner Lukas Habernig Filomena Broeskamp Doris Ruli F Nora Vögtle Manolis Vlachos Francesca Macchi Victoria Küttner Didac Carmona‐Gutierrez Tobias Eisenberg Julia Ring Maria Markaki Asli Aras Taskin Stefan Benke Christoph Ruckenstuhl Ralf Braun Chris Van den Haute Tine Bammens Anke van der Perren Kai‐Uwe Fröhlich Joris Winderickx Guido Kroemer Veerle Baekelandt Nektarios Tavernarakis Gabor G Kovacs Jörn Dengjel Chris Meisinger Stephan J Sigrist Frank Madeo 《The EMBO journal》2013,32(23):3041-3054
Malfunctioning of the protein α‐synuclein is critically involved in the demise of dopaminergic neurons relevant to Parkinson's disease. Nonetheless, the precise mechanisms explaining this pathogenic neuronal cell death remain elusive. Endonuclease G (EndoG) is a mitochondrially localized nuclease that triggers DNA degradation and cell death upon translocation from mitochondria to the nucleus. Here, we show that EndoG displays cytotoxic nuclear localization in dopaminergic neurons of human Parkinson‐diseased patients, while EndoG depletion largely reduces α‐synuclein‐induced cell death in human neuroblastoma cells. Xenogenic expression of human α‐synuclein in yeast cells triggers mitochondria‐nuclear translocation of EndoG and EndoG‐mediated DNA degradation through a mechanism that requires a functional kynurenine pathway and the permeability transition pore. In nematodes and flies, EndoG is essential for the α‐synuclein‐driven degeneration of dopaminergic neurons. Moreover, the locomotion and survival of α‐synuclein‐expressing flies is compromised, but reinstalled by parallel depletion of EndoG. In sum, we unravel a phylogenetically conserved pathway that involves EndoG as a critical downstream executor of α‐synuclein cytotoxicity. 相似文献
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Systemically administered neuregulin‐1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease 下载免费PDF全文
Candan Depboylu Thomas W. Rösler Anderson de Andrade Wolfgang H. Oertel Günter U. Höglinger 《Journal of neurochemistry》2015,133(4):590-597
Previously, we demonstrated that systemically injected extracellular domain of neuregulin‐1β1 (Nrg1β1), a nerve growth and differentiation factor, passes the blood‐brain barrier and rescues dopaminergic neurons of substantia nigra in the 6‐hydroxydopamine‐mouse model of Parkinson's disease (PD). Here, we studied the effects of peripherally administered Nrg1β1 in another toxin‐based mouse model of PD. For this purpose, (i) nigrostriatal pathway injury was induced by treatment of adult wild‐type mice with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in acute and subchronic paradigms; and (ii) Nrg1β1 or saline (control) were administered 1 h before each MPTP injection. We found that Nrg1β1 significantly reduced the loss of nigral dopaminergic neurons in both intoxication paradigms (7 days post‐injection). However, Nrg1β1 did not reverse MPTP‐induced decrease in dopamine levels and dopaminergic fibers in the striatum. We also show that MPTP conversion to its toxic metabolite 1‐methyl‐4‐phenylpyridinium as well as levels of dopamine transporter, mediating intracellular uptake of 1‐methyl‐4‐phenylpyridinium, are unaffected by Nrg1β1. Finally, neuroprotective properties of Nrg1β1 on nigral dopaminergic neurons are specifically mediated by ErbB4 as revealed through the study of ErbB4 knockout mice. In conclusion, systemically administered Nrg1β1 protects midbrain dopaminergic neurons against this PD‐related toxic insult. Thus, Nrg1β1 may have a benefit in the treatment of PD patients.
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Carola Rotermund Felicia M. Truckenmüller Heinrich Schell Philipp J. Kahle 《Journal of neurochemistry》2014,131(6):848-858
Parkinson's disease (PD) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid‐like fibrillar and serine‐129 phosphorylated (pS129) α‐synuclein (AS). To study if diet‐induced obesity could be an environmental risk factor for PD‐related α‐synucleinopathy, transgenic (TG) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet (HFD). The TG mice became obese and glucose‐intolerant, as did the wild‐type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α‐synucleinopathy as detected by immunostaining with antibodies against pathology‐associated pS129. Amyloid‐like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver‐positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro‐survival signaling intermediate Akt was reduced in younger TG mice after HFD. Thus, diet‐induced obesity may be an environmental risk factor for the development of α‐synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated.
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Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/α‐synuclein complex by Hip 下载免费PDF全文
August Andersson Annemieke T van der Goot Shang‐Te Hsu Rafael Fernández‐Montesinos Jannie de Jong Tjakko J van Ham Ellen A Nollen David Pozo John Christodoulou Christopher M Dobson 《The EMBO journal》2009,28(23):3758-3770
The ATP‐dependent protein chaperone heat‐shock protein 70 (Hsp70) displays broad anti‐aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of α‐synuclein (αSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation‐prone polypeptides. We show a nucleotide‐dependent interaction between Hsp70 and αSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with αSyn. Such a co‐aggregation phenomenon can be prevented in vitro by the co‐chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of αSyn aggregation. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration. 相似文献
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Long‐lasting pathological consequences of overexpression‐induced α‐synuclein spreading in the rat brain 下载免费PDF全文
Increased expression of α‐synuclein can initiate its long‐distance brain transfer, representing a potential mechanism for pathology spreading in age‐related synucleinopathies, such as Parkinson's disease. In this study, the effects of overexpression‐induced α‐synuclein transfer were assessed over a 1‐year period after injection of viral vectors carrying human α‐synuclein DNA into the rat vagus nerve. This treatment causes targeted overexpression within neurons in the dorsal medulla oblongata and subsequent diffusion of the exogenous protein toward more rostral brain regions. Protein advancement and accumulation in pontine, midbrain, and forebrain areas were contingent upon continuous overexpression, because death of transduced medullary neurons resulted in cessation of spreading. Lack of sustained spreading did not prevent the development of long‐lasting pathological changes. Particularly remarkable were findings in the locus coeruleus, a pontine nucleus with direct connections to the dorsal medulla oblongata and greatly affected by overexpression‐induced transfer in this model. Data revealed progressive degeneration of catecholaminergic neurons that proceeded long beyond the time of spreading cessation. Neuronal pathology in the locus coeruleus was accompanied by pronounced microglial activation and, at later times, astrocytosis. Interestingly, microglial activation was also featured in another region reached by α‐synuclein transfer, the central amygdala, even in the absence of frank neurodegeneration. Thus, overexpression‐induced spreading, even if temporary, causes long‐lasting pathological consequences in brain regions distant from the site of overexpression but anatomically connected to it. Neurodegeneration may be a consequence of severe protein burden, whereas even a milder α‐synuclein accumulation in tissues affected by protein transfer could induce sustained microglial activation. 相似文献
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Ning Zhang Wen‐Yan Hua Yi‐Xian Huang Ping‐Wei Di Tingting Huang Xing‐Shun Xu Chun‐Feng Liu Li‐Fang Hu Wei‐Feng Luo 《Journal of neurochemistry》2012,123(5):876-885
Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6‐hydroxydopamine (6‐OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) in the lesioned striata of 6‐OHDA‐lesioned rats was dramatically reduced as compared with sham‐operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3β activity caused by 6‐OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3β phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6‐OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3β signaling. 相似文献
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Measurements of auto‐antibodies to α‐synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease 下载免费PDF全文
Rizwan S. Akhtar Joseph P. Licata Kelvin C. Luk Leslie M. Shaw John Q. Trojanowski Virginia M.‐Y. Lee 《Journal of neurochemistry》2018,145(6):489-503
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Binding to serine 65‐phosphorylated ubiquitin primes Parkin for optimal PINK1‐dependent phosphorylation and activation 下载免费PDF全文
Agne Kazlauskaite R Julio Martínez‐Torres Scott Wilkie Atul Kumar Julien Peltier Alba Gonzalez Clare Johnson Jinwei Zhang Anthony G Hope Mark Peggie Matthias Trost Daan MF van Aalten Dario R Alessi Alan R Prescott Axel Knebel Helen Walden Miratul MK Muqit 《EMBO reports》2015,16(8):939-954
Mutations in the mitochondrial protein kinase PINK1 are associated with autosomal recessive Parkinson disease (PD). We and other groups have reported that PINK1 activates Parkin E3 ligase activity both directly via phosphorylation of Parkin serine 65 (Ser65)—which lies within its ubiquitin‐like domain (Ubl)—and indirectly through phosphorylation of ubiquitin at Ser65. How Ser65‐phosphorylated ubiquitin (ubiquitinPhospho‐Ser65) contributes to Parkin activation is currently unknown. Here, we demonstrate that ubiquitinPhospho‐Ser65 binding to Parkin dramatically increases the rate and stoichiometry of Parkin phosphorylation at Ser65 by PINK1 in vitro. Analysis of the Parkin structure, corroborated by site‐directed mutagenesis, shows that the conserved His302 and Lys151 residues play a critical role in binding of ubiquitinPhospho‐Ser65, thereby promoting Parkin Ser65 phosphorylation and activation of its E3 ligase activity in vitro. Mutation of His302 markedly inhibits Parkin Ser65 phosphorylation at the mitochondria, which is associated with a marked reduction in its E3 ligase activity following mitochondrial depolarisation. We show that the binding of ubiquitinPhospho‐Ser65 to Parkin disrupts the interaction between the Ubl domain and C‐terminal region, thereby increasing the accessibility of Parkin Ser65. Finally, purified Parkin maximally phosphorylated at Ser65 in vitro cannot be further activated by the addition of ubiquitinPhospho‐Ser65. Our results thus suggest that a major role of ubiquitinPhospho‐Ser65 is to promote PINK1‐mediated phosphorylation of Parkin at Ser65, leading to maximal activation of Parkin E3 ligase activity. His302 and Lys151 are likely to line a phospho‐Ser65‐binding pocket on the surface of Parkin that is critical for the ubiquitinPhospho‐Ser65 interaction. This study provides new mechanistic insights into Parkin activation by ubiquitinPhospho‐Ser65, which could aid in the development of Parkin activators that mimic the effect of ubiquitinPhospho‐Ser65. 相似文献
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Jean‐Marc Taymans Mark R. Cookson 《BioEssays : news and reviews in molecular, cellular and developmental biology》2010,32(3):227-235
Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, α‐synuclein (SNCA) and leucine‐rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA‐positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins. 相似文献