Optical Reporters for the Conformation of α-Synuclein Reveal a Specific Interaction with Mitochondria

Nakamura, Ken; Nemani, Venu M.; Wallender, Erika K.; Kaehlcke, Katrin; Ott, Melanie; Edwards, Robert H.

doi:10.1523/jneurosci.3088-08.2008

Cited by 195 publications

(185 citation statements)

References 97 publications

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“…␣-Synuclein Specifically Disrupts Mitochondrial MorphologyConsidering the specific interaction of ␣-synuclein with mitochondrial membranes (27), we first assessed the potential effect of synuclein on mitochondrial morphology. Using HeLa cells because of their flat shape, large size, and dispersed tubular mitochondria, we cotransfected wild type human ␣-synuclein with a mitochondrially targeted enhanced green fluorescent protein (mitoGFP) and the blue fluorescent protein azurite as an independent reporter for transfection.…”

Section: Resultsmentioning

confidence: 99%

“…Synuclein preferentially binds to mitochondria in vitro (27), suggesting that the effect on mitochondrial fragmentation may result from a direct interaction. To test this possibility, we introduced a dual myristoylation/palmitoylation sequence from Lyn kinase (61) that targets synuclein to the secretory pathway.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

“…In addition, recent observations have begun to suggest a direct interaction of synuclein with mitochondria (21,(23)(24)(25)(26). We have previously found that synuclein binds specifically to mitochondria rather than other organelles (27), and the amount of synuclein localized to the mitochondria of substantia nigra neurons increases dramatically in PD (24). Does ␣-synuclein influence the behavior of mitochondria?…”

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confidence: 99%

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Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Nakamura

Nemani

Azarbal

et al. 2011

Journal of Biological Chemistry

540

556

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The protein ␣-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of ␣-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by ␣-than ␤-or ␥-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. ␣-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.Many observations have implicated mitochondria in the pathogenesis of PD.2 Mitochondria from the substantia nigra of affected patients show a selective reduction in the activity of respiratory chain complex I (1). Somatic mutations also accumulate with age and PD in the mitochondrial DNA of substantia nigra neurons (2). In addition, the neurotoxins MPTP and rotenone, which produce models of PD, both act by disrupting mitochondrial function. Genetic evidence further supports a primary role for mitochondria in the pathogenesis of PD. Mutations in parkin and the mitochondrial kinase PINK1 both cause autosomal recessive PD (3), and these genes appear required for the normal clearance of defective mitochondria by autophagy (4). However, the molecular mechanisms responsible for mitochondrial dysfunction in the much more common sporadic forms of PD have remained unclear. Several observations suggest a central role for the protein ␣-synuclein in the pathogenesis of sporadic PD. Point mutations in synuclein produce a rare autosomal dominant form of PD (5-7), indicating a causative role for the protein. ␣-Synuclein also accumulates in the Lewy bodies and dystrophic neurites of essentially all patients with idiopathic PD (8), implicating the protein in sporadic as well as familial forms of the disease. Furthermore, duplication and particularly triplication of the SNCA (␣-synuclein) gene cause a severe, highly penetrant form of PD (9, 10), indicating a dose-dependent pathogenic role for the wild type protein when overexpressed and suggesting that the accumulation of synuclein in sporadic PD is the primary pathogenic event. However, the mechanism by which ␣-synuclein causes PD remains poorly understood. Expressed in yeast and Drosophila, human ␣-synuclein produces severe toxicity (11-14), but these model organisms lack endogenous synuclein, and the overexpression of wild type synuclein in mammalian systems causes remarkably little if any consistent toxicity (15-18).Althou...

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Section: Resultsmentioning

confidence: 99%

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Nakamura

Nemani

Azarbal

et al. 2011

Journal of Biological Chemistry

540

556

View full text Add to dashboard Cite

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“…AT1.03 YEMK and AT R122K/R126K fluorescence resonance energy transfer (FRET) sensors (which use a variant of CFP 5 (mseCFP) as the donor fluorophore and YFP (circularly permuted monomeric Venus) as the acceptor fluorophore, surrounding an ATP-binding protein) were the kind gifts from Hiromi Imamura (Kyoto University) and Hiroyuki Noji (Osaka University) (10). VGLUT1-pHluorin, mCherry-synaptophysin, mitoGFP, and the direct CFP-YFP fusion have been described (9,(11)(12)(13). Mito-FarRed (TagRFP657 fused to the mitochondrial targeting sequence, cytochrome c oxidase subunit VIII) and mTagBFP (used to make mito-mTagBFP) were kind gifts from Vladislav Verkhusha (Albert Einstein College of Medicine) (14,15), and Cre recombinase (Cre) was from Addgene.…”

Section: Methodsmentioning

confidence: 99%

The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

Pathak

Shields

Mendelsohn

et al. 2015

Journal of Biological Chemistry

259

214

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Background:The ATP requirements of synaptic vesicle release are poorly understood. Results: Mitochondrially derived ATP supports the function of boutons with and without mitochondria. Respiratory dysfunction selectively blocks the reinternalization of synaptic vesicles. Conclusion: ATP diffuses rapidly in axons to support synaptic vesicle recycling. Mitochondrial dysfunction decreases synaptic energy and impairs function. Significance: Understanding energy requirements will help determine how energy failure contributes to neurodegeneration.

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“…Abbreviations: 4E-BP, eukaryotic initiation factor 4E-binding protein; GBA, glucocerebrosidase; HTRA2, serine protease HTRA2, mitochondrial; LRRK2, leucine-rich repeat kinase 2; PD, Parkinson's disease; PINK1, PTEN-induced kinase 1; TRAP1, TNFR-associated protein 1. synapse. 76 Alpha-synuclein binds to membranes and inhibits fusion, leading to fragmentation. 77 This action of alpha-synuclein is independent of the PINK1-parkin mitophagy pathway, but can be rescued by overexpression of parkin, PINK1, or DJ1 but not the mutated forms of these genes.…”

Section: Alpha-synucleinmentioning

confidence: 99%

Mitochondrial Pathology in Parkinson's Disease

Schapira

2011

Mount Sinai J Medicine

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The last 25 years have witnessed remarkable advances in our understanding of the etiology and pathogenesis of Parkinson's disease. The ability to undertake detailed biochemical analyses of the Parkinson's disease postmortem brain enabled the identification of defects of mitochondrial and free‐radical metabolism. The discovery of the first gene mutation for Parkinson's disease, in alpha‐synuclein, ushered in the genetic era for the disease and the subsequent finding of several gene mutations causing parkinsonism, 15 at the time of writing. Technological advances both in sequencing technology and software analysis have allowed association studies of sufficiently large size accurately to describe genes conferring an increased risk for Parkinson's disease. What has been so surprising is the convergence of these 2 separate disciplines (biochemistry and genetics) in terms of reinforcing the importance of the same pathways (ie, mitochondrial dysfunction and free‐radical metabolism). Other pathways are also important in pathogenesis, including protein turnover, inflammation, and post‐translational modification, particularly protein phosphorylation and ubiquitination. However, even these additional pathways overlap with each other and with those of mitochondrial dysfunction and oxidative stress. This review explores these concepts with particular relevance to mitochondrial involvement. Mt Sinai J Med 78:872–881, 2011. © 2011 Mount Sinai School of Medicine

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Optical Reporters for the Conformation of α-Synuclein Reveal a Specific Interaction with Mitochondria

Cited by 195 publications

References 97 publications

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

Mitochondrial Pathology in Parkinson's Disease

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