A Novel Mechanism of Interaction between α-Synuclein and Biological Membranes

Kim, Yoon Suk; Laurine, Emmanuelle; Woods, Wendy S.; Lee, Seung-Jae

doi:10.1016/j.jmb.2006.05.004

Cited by 48 publications

(42 citation statements)

References 48 publications

(55 reference statements)

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“…The simplest explanation is that synuclein binding to native mitochondrial membranes is highly dynamic and that formaldehyde stabilizes binding by cross-linking. This is consistent with data suggesting that synuclein binding to native membranes is rapidly reversible [24,50]. Formaldehyde had no effect on the pH of the binding reaction (see Materials and Methods), demonstrating that reduction to pH 6.0 is sufficient for synuclein binding in vitro.…”

Section: Synuclein Binds To Purified Mitochondria At Low Phsupporting

confidence: 91%

“…The requirement for formaldehyde (this study) or other cross-linking reagents in stabilizing these interactions underscores the dynamic nature of synuclein binding to native membranes [24,50], and likely explains our inability to observe significant mitochondrial binding at low pH by subcellular fractionation in the absence of cross-linking (data not shown). It can be questioned whether the observed binding of synuclein to mitochondria is physiologically relevant.…”

Section: Discussionmentioning

confidence: 79%

“…6F). It is unclear whether the loss of pH/formaldehyde sensitivity was due to extraction of an important protein component from the membranes, to changes in composition or shape of the exposed liposome surface, or to the dynamic nature of synuclein binding to native versus synthetic membranes [50]. Nevertheless, these results suggest that low pH may increase cardiolipin levels exposed to the outer mitochondrial membrane and facilitate synuclein binding.…”

Section: Synuclein Binds To Purified Mitochondria At Low Phmentioning

confidence: 99%

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Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

179

164

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Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.

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Section: Synuclein Binds To Purified Mitochondria At Low Phsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 79%

Section: Synuclein Binds To Purified Mitochondria At Low Phmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

179

164

View full text Add to dashboard Cite

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“…Previous studies have shown that the N-terminal KTKEGV imperfect ␣-helical motifs are involved in membrane binding (Davidson et al, 1998;Perrin et al, 2000;Kim et al, 2006), but it is unclear if they are required for ␣-syn localization to the plasma membrane. To test this possibility, we generated yeast cell lines expressing ␣-syn-EGFP fusion proteins with either the first 57 amino acids alone (1-57-EGFP) or with these residues deleted (58-140-EGFP; Figures 1A and 2A).…”

Section: ␣-Synuclein Accumulation In the Cytoplasm Requires Both The mentioning

confidence: 99%

“…Furthermore, the N-terminus of ␣-syn contains several imperfect KTKEGV repeats (Maroteaux et al, 1988;George et al, 1995;Weinreb et al, 1996), which are thought to mediate binding to membranes by interacting with phospholipids and shifting from a random coil to an ␣-helical conformation (Davidson et al, 1998;Perrin et al, 2000;Kim et al, 2006). Interestingly, the PD familial mutation A30P in ␣-syn showed reduced binding to membranes due to the Ala3 Prosubstitution in repeat 2, which disrupts membrane interaction (Jensen et al, 1998;Cole et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Soper¹,

Roy²,

Stieber³

et al. 2008

MBoC

146

168

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Aggregated ␣-synuclein (␣-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson's disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, ␣-syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human ␣-syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast ␣-syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that ␣-syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed ␣-syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of ␣-syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB-containing neurons of PD brains, ␣-syn-mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related synucleinopathies. INTRODUCTIONParkinson's disease (PD) is the most prevalent neurodegenerative movement disorder and is characterized by bradykinesia, rigidity, postural instability, and resting tremor (Galvin et al., 2001;Forman et al., 2005), as well as by the loss of dopaminergic neurons and presence of neuronal inclusions, known as Lewy bodies (LBs) and Lewy neurites (Forman et al., 2005). The identification of an ␣-syn gene (SNCA) mutation associated with autosomal dominant PD (Polymeropoulos et al., 1997), and the identification of fibrillar ␣-syn as the principal component of LB pathology (Spillantini et al., 1997), indicate that the LBs formed by ␣-syn define classic PD and are implicated in disease pathogenesis. The subsequent identification of additional disease-linked SNCA mutations (Polymeropoulos et al., 1997;Kruger et al., 1998;Zarranz et al., 2004), as well as replications of the SNCA gene (Singleton et al., 2003;Chartier-Harlin et al., 2004), indicate that both mutant ␣-syn and increased expression of wildtype (WT) ␣-syn can cause neurodegeneration.In addition to PD, filamentous ␣-syn inclusions have been detected in other neurodegenerative diseases including the LB variant of Alzheimer's disease, dementia with LBs, neurodegeneration with brain iron accumulation type-1, and multiple system atrophy, which are collectively known as synucleinopathies (Spillantini et al., 1997;Duda et al., 2000). ␣-syn fibrils exhibit properties of amyloid (Spillantini et al., 1998), and ␣-syn assembles into amyloid fibrils in vitro (Han et al., 1995;Giasson et al., 1999), whereas SNCA mutations can accelerate ␣-syn fibrillization (Conway et al., 1998;Greenbaum et al., 2005). Therefore, it is plausible that ␣-syn misfolds and aggregates into amyloid fibrils that are neurotoxic and play a cau...

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