Chaperone-like activities of α-synuclein: α-Synuclein assists enzyme activities of esterases

Ahn, Myoung Hwan; Kim, Seungbum; Kang, Mira; Ryu, Yeon‐Woo; Kim, T. Doohun

doi:10.1016/j.bbrc.2006.05.213

Cited by 50 publications

(41 citation statements)

References 26 publications

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“…Cardiolipin is thought to be responsible for maintaining the physical connectivity of mitochondrial electron transport chain complexes involved in oxidative phosphorylation (36). Several lines of evidence suggest that constitutive ␣-synuclein may be a chaperone protein and can also bind to cardiolipin (3,(37)(38)(39). The present study suggests that mitochondria localized ␣-synuclein is in association with complex I and lowering the endogenous mitochondrial levels by siRNA may impair connectivity between complex I and III in human DAN cell culture.…”

Section: Discussionmentioning

confidence: 49%

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Devi

Raghavendran

Prabhu

et al. 2008

Journal of Biological Chemistry

975

926

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␣-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human ␣-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of ␣-synuclein. Mitochondrial imported ␣-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type ␣-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial ␣-synuclein with A53T mutation as compared with wild-type ␣-synuclein. Importantly, ␣-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ϳ14-kDa ␣-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of ␣-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and ␣-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of ␣-synuclein with complex I. These results provide evidence that mitochondrial accumulated ␣-synuclein may interact with complex I and interfere with its functions. Parkinson disease (PD)2 is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta.

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Section: Discussionmentioning

confidence: 49%

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Devi

Raghavendran

Prabhu

et al. 2008

Journal of Biological Chemistry

975

926

View full text Add to dashboard Cite

show abstract

“…In the analyses shown here, ERD10 and ERD14 demonstrated marked effects on the prevention of aggregation/deactivation of protein substrates. A comparison of related data published in the literature, such as for periplasmic disulfide isomerase of Gram-negative bacteria (DsbC; Chen et al, 1999), a-synuclein (Kim et al, 2000;Souza et al, 2000;Ahn et al, 2006), HSP90 (Minami et al, 2001), or tubulin (Guha et al, 1998), makes it safe to conclude that ERD10 and ERD14 are chaperones of commensurate potency to previously described representatives of this functional class. The significance of the effect is underlined by the fact that it far exceeds that of BSA and in several cases is commensurate with, or even exceeds, that exerted by HSP90.…”

Section: Discussionmentioning

confidence: 98%

Chaperone Activity of ERD10 and ERD14, Two Disordered Stress-Related Plant Proteins

et al. 2008

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ERD10 and ERD14 (for early response to dehydration) proteins are members of the dehydrin family that accumulate in response to abiotic environmental stresses, such as high salinity, drought, and low temperature, in Arabidopsis (Arabidopsis thaliana). Whereas these proteins protect cells against the consequences of dehydration, the exact mode(s) of their action remains poorly understood. Here, detailed evidence is provided that ERD10 and ERD14 belong to the family of intrinsically disordered proteins, and it is shown in various assays that they act as chaperones in vitro. ERD10 and ERD14 are able to prevent the heat-induced aggregation and/or inactivation of various substrates, such as lysozyme, alcohol dehydrogenase, firefly luciferase, and citrate synthase. It is also demonstrated that ERD10 and ERD14 bind to acidic phospholipid vesicles without significantly affecting membrane fluidity. Membrane binding is strongly influenced by ionic strength. Our results show that these intrinsically disordered proteins have chaperone activity of rather wide substrate specificity and that they interact with phospholipid vesicles through electrostatic forces. We suggest that these findings provide the rationale for the mechanism of how these proteins avert the adverse effects of dehydration stresses.

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“…Cell death was linearly correlated with the concentration of exogenous α-synuclein and was amplified when the applied protein also contained soluble oligomers (Albani et al, 2004;Du et al, 2003;Sung et al, 2001;Zhang et al, 2005). Application of recombinant monomeric or aggregated α-synuclein also revealed that this protein can be readily be uptaken by neuronal cells or even neural stem cells in culture (Ahn, Kim, Kang, Ryu, & Kim, 2006;Desplats et al, 2009;H. J. Lee et al, 2008;Luk et al, 2009;Sung et al, 2001).…”

Section: Effects Of Extracellular α-Synuclein On Cellular Homeostasismentioning

confidence: 99%

Effects of Alpha-Synuclein on Cellular Homeostasis

Vekrellis¹,

Minakaki²,

Emmanouilidou³

2011

Etiology and Pathophysiology of Parkinson's Disease

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Chaperone-like activities of α-synuclein: α-Synuclein assists enzyme activities of esterases

Cited by 50 publications

References 26 publications

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Chaperone Activity of ERD10 and ERD14, Two Disordered Stress-Related Plant Proteins

Effects of Alpha-Synuclein on Cellular Homeostasis

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