Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole, Nelson B.; DiEuliis, Diane; Leo, Paul; Mitchell, Drake C.; Nussbaum, Robert L.

doi:10.1016/j.yexcr.2008.03.012

Cited by 176 publications

(173 citation statements)

References 69 publications

(80 reference statements)

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“…As described before, oxidative damage to alphaͲsyn affects its aggregation Ͳ an effect that partially explains the cellular toxicity of the protein. AlphaͲsyn contains an NͲterminal mitochondrialͲtargeting sequence [181], and cytosol acidification or alphaͲsyn overexpression can lead the protein to localize to mitochondria [182,183], resulting in complex I impairment and increased ROS production [181], increased protein tyrosine nitration and decreased mitochondrial transmembrane potential [184]. In addition, it was shown that human embryonic kidney cells that overexpress alphaͲsyn, show enhanced susceptibility to cell death and have lower ATP levels compared to control cells [183].…”

Section: Alphaǧsynuclein (Snca)mentioning

confidence: 99%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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Section: Alphaǧsynuclein (Snca)mentioning

confidence: 99%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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“…Low pH is furthermore associated with PD through both the exosomes via the lysosomal pathway 42 and oxidative or metabolic stress in mitochondria. 43 The contrast in NR is determined by the differences in the scattering length density (SLD) values for the various sample components. Hydrogen and deuterium have markedly different SLD values, and with a change in the degree of deuteration of lipids, protein, and solvent, the contribution from the different components to neutron scattering of a sample can be matched so that the scattering from a specific part, region, or component of interest is highlighted.…”

mentioning

confidence: 99%

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Hellstrand

Grey

Ainalem

et al. 2013

ACS Chem. Neurosci.

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An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniquesquartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.

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“…The gene coding for -synuclein has a terminal sequence with mitochondrial target [23]. Cytosol acidifi cation or overexpression of -synuclein can lead to accumulation of this protein in mitochondria [24].…”

Section: Risk Level Environmental Agentmentioning

confidence: 99%

Genes involved in the development of Parkinson

Teixeira¹,

Cardoso²

2017

Open J Parkinsons Dis Treatm

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Background: Parkinson's disease is the second most important neurodegenerative disorder, affecting 3% of individuals older than 80 years of age. Main clinical symptoms are resting tremor, postural instability, bradykinesia and rigidity, with a good response to levodopa therapy. Purpose of the study:The main goal of this work is to make a deep analysis on the genetic factors and kind of heritage involved in the development of Parkinson. Main fi ndings:Over the last years, numerous studies allowed to confirm the unquestionable contribution of genetic factors to the complex pathogenesis of this disease. Highly penetrant mutations producing rare, monogenic forms of the disease have been identifi ed in singular genes such as SNCA, Parkin, DJ-1, PINK1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA genes were identifi ed as strong risk factors for Parkinson's disease in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for Parkinson's disease.Investigating Mendelian forms of Parkinson disease has provided precious insight into the pathophysiology that underlies the more common idiopathic form of this disorder. Conclusions:The challenge over the next decade will be to get more data that strengthens the already available knowledge concerning genetics on Parkinson's disease, through the discovery of biological consequences of risk variants. Moreover, it is also expected that the advent of genome-wide association studies and the implementation of new research technologies will help in the identifi cation of novel risk variants for the sporadic forms of Parkinson disease.

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Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cited by 176 publications

References 69 publications

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Genes involved in the development of Parkinson

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