Plasma membrane ion permeability induced by mutant α‐synuclein contributes to the degeneration of neural cells

Furukawa, Koichi; Matsuzaki-Kobayashi, Michiko; Hasegawa, Takafumi; Kikuchi, Akio; Sugeno, Naoto; Itoyama, Yasuto; Wang, Yue; Yao, Pamela J.; Bushlin, Ittai; Takeda, Atsushi

doi:10.1111/j.1471-4159.2006.03803.x

Cited by 105 publications

(102 citation statements)

References 30 publications

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“…Specifically, the His residue located at position 50 in the a-syn monomer is a possible candidate for interaction with Zn 2+ ions because it is situated near the putative pore region of the a-syn pentamer. The increased ion channel activity observed in the present study is in agreement with recent results showing that human neuronal cells expressing mutant a-syn have high plasma membrane ion permeability that was sensitive to calcium chelators [47]. Taken together, these results support the contention that a-syn aggregates might form functional ion-permeable channels that in turn might play a role in the mechanisms of neurodegeneration in LBD.…”

Section: Discussionsupporting

confidence: 93%

“…1A,B), the initial two curved helical N-terminal domains (helices N and C) of a-syn transform into three uncurved N-terminal helical structures. The third helical region appears when the second curved helix (aa 46-84) converts into two uncurved helices, helix 2 (aa [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] and helix 3 (aa 74-84), linked by aa [64][65][66][67][68][69][70][71][72][73] (Fig. 1A,B).…”

Section: Resultsmentioning

confidence: 99%

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Dynamics of α‐synuclein aggregation and inhibition of pore‐like oligomer development by β‐synuclein

et al. 2007

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In recent years, new hope for understanding the pathogenesis of Parkinson's disease (PD) and Lewy body dementia (LBD) has emerged with the discovery of mutations and duplications in the a-synuclein (a-syn) gene that are associated with rare familial forms of Parkinsonism [1][2][3]. Moreover, it has been shown that a-syn is centrally involved in the pathogenesis of both sporadic and inherited forms of PD and LBD because this molecule accumulates in Lewy bodies (LBs) [4][5][6], synapses, and axons, and its expression in transgenic (tg) mice [7][8][9] and Drosophila [10] mimics several aspects of PD.The mechanisms through which a-syn leads to neurodegeneration and the characteristic symptoms of LBD are unclear. However, recent evidence indicates that abnormal accumulation of misfolded a-syn in the Accumulation of a-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson's disease and Lewy body dementia. In contrast, b-synuclein (b-syn), a close homologue, does not aggregate and reduces a-synuclein (a-syn)-related pathology. Although considerable information is available about the conformation of a-syn at the initial and end stages of fibrillation, less is known about the dynamic process of a-syn conversion to oligomers and how interactions with antiaggregation chaperones such as b-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of a-syn showed that a-syn homodimers can adopt nonpropagating (head-to-tail) and propagating (head-to-head) conformations. Propagating a-syn dimers on the membrane incorporate additional a-syn molecules, leading to the formation of pentamers and hexamers forming a ring-like structure. In contrast, b-syn dimers do not propagate and block the aggregation of a-syn into ring-like oligomers. Under in vitro cell-free conditions, a-syn aggregates formed ring-like structures that were disrupted by b-syn. Similarly, cells expressing a-syn displayed increased ion current activity consistent with the formation of Zn 2+ -sensitive nonselective cation channels. These results support the contention that in Parkinson's disease and Lewy body dementia, a-syn oligomers on the membrane might form pore-like structures, and that the beneficial effects of b-synuclein might be related to its ability to block the formation of pore-like structures.Abbreviations aa, amino acid; a-syn, a-synuclein; b-syn, b-synuclein; GFP, green fluorescent protein; LBD, Lewy body disease; PD, Parkinson's disease; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; tg, transgenic.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Dynamics of α‐synuclein aggregation and inhibition of pore‐like oligomer development by β‐synuclein

et al. 2007

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“…This suggests that intracellular ␣-syn does not contribute under these experimental conditions to the pore formation, although other studies have shown that cells expressing mutant ␣-syn[A53T] have a higher plasma membrane permeability (Furukawa et al, 2006).…”

Section: Discussionmentioning

confidence: 69%

Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding

Danzer

Haasen²,

Karow³

et al. 2007

J. Neurosci.

716

778

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Aggregation of ␣-synuclein (␣-syn) has been linked to the pathogenesis of Parkinson's disease (PD) and other neurodegenerative diseases. Increasing evidence suggests that prefibrillar oligomers and protofibrils, rather than mature fibrils of ␣-syn, are the pathogenic species in PD. Despite extensive effort on studying oligomerization of ␣-syn, no studies have compared different oligomer species directly on a single-particle level and investigated their biological effects on cells. In this study, we applied a novel highly sensitive single molecule detection system that allowed a direct comparison of different oligomer types. Furthermore, we studied biological effects of different oligomer types on cells. For this purpose, we developed new oligomerization protocols, that enabled the use of these different oligomers in cell culture. We found that all of our three aggregation protocols resulted in heterogeneous populations of oligomers. Some types of oligomers induced cell death via disruption of cellular ion homeostasis by a presumably pore-forming mechanism. Other oligomer types could directly enter the cell resulting in increased ␣-syn aggregation. Based on our results, we propose that under various physiological conditions, heterogeneous populations of oligomeric forms will coexist in an equilibrium. These different oligomer types lead directly or indirectly to cell damage. Our data indicate that inhibition of early ␣-syn aggregation events would consequently prevent all ␣-syn oligomer related toxicities. This has important implications for the development of disease-modifying drugs for the treatment of PD and other synucleinopathies.

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“…1). In solution and at high concentrations (Ͼ200 M), ␣-Syn spontaneously forms annular pore-like structures (20,21) that, when added externally to the culture medium, can cause toxic ion leakage in neuroblastoma cells (22).…”

mentioning

confidence: 99%

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

Hinault

Cuendet

Mattoo

et al. 2010

Journal of Biological Chemistry

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␣-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable ␤-sheet enriched toroid-shaped ␣-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured ␣-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by ␣-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.

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Plasma membrane ion permeability induced by mutant α‐synuclein contributes to the degeneration of neural cells

Cited by 105 publications

References 30 publications

Dynamics of α‐synuclein aggregation and inhibition of pore‐like oligomer development by β‐synuclein

Dynamics of α‐synuclein aggregation and inhibition of pore‐like oligomer development by β‐synuclein

Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding

Stable α-Synuclein Oligomers Strongly Inhibit Chaperone Activity of the Hsp70 System by Weak Interactions with J-domain Co-chaperones

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