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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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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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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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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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Nora Wender Jan Hegermann Bettina Brunner Brigitte Nuscher Tim Bartels Armin Giese Klaus Beyer Stefan Eimer Konstanze F Winklhofer Christian Haass 《The EMBO journal》2010,29(20):3571-3589
Aggregation of α‐synuclein (αS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of αS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that αS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, αS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age‐dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous αS. In contrast, siRNA‐mediated downregulation of αS results in elongated mitochondria in cell culture. αS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, αS prevents fusion of differently labelled mitochondrial populations. Thus, αS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of αS is rescued by coexpression of PINK1, parkin or DJ‐1 but not the PD‐associated mutations PINK1 G309D and parkin Δ1–79 or by DJ‐1 C106A. 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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Parkinson's disease (PD) is a movement neurodegenerative disorder, characterized by bradykinesia, rigidity and tremor, constituting difficulties in walking and abnormal gait. Previous research shows that Drosophila expressing human α‐synuclein A30P (A30P) develop deficits in geotaxis climbing; however, geotaxis climbing is a different movement modality from walking. Whether A30P flies would exhibit abnormal walking in a horizontal plane, a measure more relevant to PD, is not known. In this study, we characterized A30P fly walking using a high‐speed camera and an automatic behavior tracking system. We found that old but not young A30P flies exhibited walking abnormalities, specifically decreased total moving distance, distance per movement, velocity, angular velocity and others, compared with old control flies. Those features match the definition of bradykinesia. Multivariate analysis further suggested a synergistic effect of aging and A30P, resulting in a distinct pattern of walking deficits, as seen in aged A30P flies. Psychiatric problems are common in PD patients with anxiety affecting 40–69% of patients. Central avoidance is one assessment of anxiety in various animal models. We found old but not young A30P flies exhibited increased centrophobism, suggesting possible elevated anxiety. Here, we report the first quantitative measures of walking qualities in a PD fly model and propose an alternative behavior paradigm for evaluating motor functions apart from climbing assay. 相似文献
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Xue Xue Weiwei Zhang Jifeng Zhu Xiaojun Chen Sha Zhou Zhipeng Xu Gang Hu Chuan Su 《Journal of cellular and molecular medicine》2019,23(4):2568-2582
Aquaporin‐4 (AQP4), the main water‐selective membrane transport protein in the brain, is localized to the astrocyte plasma membrane. Following the establishment of a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson's disease (PD) model, AQP4‐deficient (AQP4?/?) mice displayed significantly stronger microglial inflammatory responses and remarkably greater losses of tyrosine hydroxylase (TH+)‐positive neurons than did wild‐type AQP4 (AQP4+/+) controls. Microglia are the most important immune cells that mediate immune inflammation in PD. However, recently, few studies have reported why AQP4 deficiency results in more severe hypermicrogliosis and neuronal damage after MPTP treatment. In this study, transforming growth factor‐β1 (TGF‐β1), a key suppressive cytokine in PD onset and development, failed to increase in the midbrain and peripheral blood of AQP4?/? mice after MPTP treatment. Furthermore, the lower level of TGF‐β1 in AQP4?/? mice partially resulted from impairment of its generation by astrocytes; reduced TGF‐β1 may partially contribute to the uncontrolled microglial inflammatory responses and subsequent severe loss of TH+ neurons in AQP4?/? mice after MPTP treatment. Our study provides not only a better understanding of both aetiological and pathogenical factors implicated in the neurodegenerative mechanism of PD but also a possible approach to developing new treatments for PD via intervention in AQP4‐mediated immune regulation. 相似文献
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Extracellular α‐synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane 下载免费PDF全文
Carla R. Pacheco Camila N. Morales Alejandra E. Ramírez Francisco J. Muñoz Scarlet S. Gallegos Pablo A. Caviedes Luis G. Aguayo Carlos M. Opazo 《Journal of neurochemistry》2015,132(6):731-741
It has been postulated that the accumulation of extracellular α‐synuclein (α‐syn) might alter the neuronal membrane by formation of ‘pore‐like structures’ that will lead to alterations in ionic homeostasis. However, this has never been demonstrated to occur in brain neuronal plasma membranes. In this study, we show that α‐syn oligomers rapidly associate with hippocampal membranes in a punctate fashion, resulting in increased membrane conductance (5 fold over control) and the influx of both calcium and a fluorescent glucose analogue. The enhancement in intracellular calcium (1.7 fold over control) caused a large increase in the frequency of synaptic transmission (2.5 fold over control), calcium transients (3 fold over control), and synaptic vesicle release. Both primary hippocampal and dissociated nigral neurons showed rapid increases in membrane conductance by α‐syn oligomers. In addition, we show here that α‐syn caused synaptotoxic failure associated with a decrease in SV2, a membrane protein of synaptic vesicles associated with neurotransmitter release. In conclusion, extracellular α‐syn oligomers facilitate the perforation of the neuronal plasma membrane, thus explaining, in part, the synaptotoxicity observed in neurodegenerative diseases characterized by its extracellular accumulation.
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Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion 下载免费PDF全文
Yousheng Xiao Xiang Chen Shuxuan Huang Guihua Li Mingshu Mo Li Zhang Chaojun Chen Wenyuan Guo Miaomiao Zhou Zhuohua Wu Luan Cen Simei Long Shaomin Li Xinling Yang Shaogang Qu Zhong Pei Pingyi Xu 《Journal of neurochemistry》2018,145(1):34-50
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HaiYue Tu BaoShi Yuan XiaoOu Hou XiaoJun Zhang ChongShuang Pei YaTing Ma YaPing Yang Yi Fan ZhengHong Qin ChunFeng Liu LiFang Hu 《Aging cell》2021,20(12)
The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson''s disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2 cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development. 相似文献
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Nicola J. Rutherford Brenda D. Moore Todd E. Golde Benoit I. Giasson 《Journal of neurochemistry》2014,131(6):859-867
The discoveries of mutations in SNCA were seminal findings that resulted in the knowledge that α‐synuclein (αS) is the major component of Parkinson's disease‐associated Lewy bodies. Since the pathologic roles of these protein inclusions and SNCA mutations are not completely established, we characterized the aggregation properties of the recently identified SNCA mutations, H50Q and G51D, to provide novel insights. The properties of recombinant H50Q, G51D, and wild‐type αS to polymerize and aggregate into amyloid were studied using (trans,trans)‐1‐bromo‐2,5‐bis‐(4‐hydroxy)styrylbenzene fluorometry, sedimentation analyses, electron microscopy, and atomic force microscopy. These studies showed that the H50Q mutation increases the rate of αS aggregation, whereas the G51D mutation has the opposite effect. However, H50Q and G51D αS could still be similarly induced to form intracellular aggregates from the exposure to exogenous amyloidogenic seeds under conditions that promote their cellular entry. Both mutant αS proteins, but especially G51D, promoted cellular toxicity under cellular stress conditions. These findings reveal that the novel pathogenic SNCA mutations, H50Q and G51D, have divergent effects on aggregation properties relative to the wild‐type protein, with G51D αS demonstrating reduced aggregation despite presenting with earlier disease onset, suggesting that these mutants promote different mechanisms of αS pathogenesis.
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Chi L. L. Pham Nigel Kirby Kathleen Wood Timothy Ryan Blaine Roberts Anna Sokolova Kevin J. Barnham Colin L. Masters Robert B. Knott Roberto Cappai Cyril C. Curtain Agata Rekas 《Proteins》2014,82(1):10-21
Alpha‐synuclein (α‐syn) forms the amyloid‐containing Lewy bodies found in the brain in Parkinson's disease. The neurotransmitter dopamine (DA) reacts with α‐syn to form SDS‐resistant soluble, non‐amyloid, and melanin‐containing oligomers. Their toxicity is debated, as is the nature of their structure and their relation to amyloid‐forming conformers of α‐syn. The small‐angle X‐ray scattering technique in combination with modeling by the ensemble optimization method showed that the un‐reacted native protein populated three broad classes of conformer, while reaction with DA gave a restricted ensemble range suggesting that the rigid melanin molecule played an important part in their structure. We found that 6 M guanidine hydrochloride did not dissociate α‐syn DA‐reacted dimers and trimers, suggesting covalent linkages. The pathological significance of covalent association is that if they are non‐toxic, the oligomers would act as a sink for toxic excess DA and α‐syn; if toxic, their stability could enhance their toxicity. We argue it is essential, therefore, to resolve the question of whether they are toxic or not. Proteins 2014; 82:10–21. © 2013 Wiley Periodicals, Inc. 相似文献
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Potential neuroprotective effect of androst‐5‐ene‐3β, 17β‐diol (ADIOL) on the striatum,and substantia nigra in Parkinson's disease rat model 下载免费PDF全文
Rania M. Salama Mariane G. Tadros Mona F. Schaalan Nevine Bahaa Ahmed M. Abdel‐tawab Amani E. Khalifa 《Journal of cellular physiology》2018,233(8):5981-6000