Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan, Julie S.; Termine, Daniel J.; Lindquist, Susan

doi:10.1073/pnas.1324209111

Cited by 13 publications

(11 citation statements)

References 43 publications

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“…Our data indicate that the presence of cholesterol in the lipid bilayer reduces the overall binding affinity for synapticlike vesicles, a result in agreement with studies in yeast showing that the inhibition of sterol synthesis enhances the vesicular localization of αS (Valastyan et al, 2014). A detailed analysis based on NMR CEST and relaxation experiments indicated that the structural effect of cholesterol on the membrane interaction by αS is restricted to residues in the NAC region, indicating a link between the overall binding affinity of the protein and the local interactions of the region 65-97.…”

Section: Discussionsupporting

confidence: 91%

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

et al. 2020

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α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson's disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles.Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65-97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65-97 to the solvent was found to induce stronger vesiclevesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-toorder equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.

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Section: Discussionsupporting

confidence: 91%

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

et al. 2020

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“…If lipid rafts mediate synuclein localization in some functionally requisite fashion, perturbation of lipid rafts or of this association could lead to synuclein mislocalization and so contribute to disease [ 148 ]. In yeast, synuclein binds to lipid rafts [ 88 ] and inhibition of sterol synthesis led to decreased plasma membrane association by synuclein, increased (aberrant) vesicular association, and increased cellular toxicity [ 224 ]. Thus, higher membrane sterol concentrations favor plasma membrane binding of synuclein, though whether this is of functional or pathological relevance remains to be determined [ 224 ].…”

Section: Synuclein/membrane Interactions In the Multifaceted Pathologmentioning

confidence: 99%

“…In yeast, synuclein binds to lipid rafts [ 88 ] and inhibition of sterol synthesis led to decreased plasma membrane association by synuclein, increased (aberrant) vesicular association, and increased cellular toxicity [ 224 ]. Thus, higher membrane sterol concentrations favor plasma membrane binding of synuclein, though whether this is of functional or pathological relevance remains to be determined [ 224 ]. Finally, given the interactions between synuclein and fatty acids discussed above, it is of interest that PUFAs are able to directly promote synuclein oligomerization both in vitro and in vivo [ 180 , 198 ].…”

Section: Synuclein/membrane Interactions In the Multifaceted Pathologmentioning

confidence: 99%

Alpha-Synuclein Function and Dysfunction on Cellular Membranes

2014

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Alpha-synuclein is a small neuronal protein that is closely associated with the etiology of Parkinson's disease. Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha-synuclein deposited in an aggregated amyloid fibril state. The normal function of alpha-synuclein is poorly understood, and the precise mechanisms by which it leads to toxicity and cell death are also unclear. Although alpha-synuclein is a highly soluble, cytoplasmic protein, it binds to a variety of cellular membranes of different properties and compositions. These interactions are considered critical for at least some normal functions of alpha-synuclein, and may well play critical roles in both the aggregation of the protein and its mechanisms of toxicity. Here we review the known features of alpha-synuclein membrane interactions in the context of both the putative functions of the protein and of its pathological roles in disease.

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“…The aggregation of AS was not enhanced when HEK239T cells were co-transfected with either 80% of AS140 or 20% of AS112 [ 136 ]. By contrast, another study carried out in a yeast model showed that, although expression of AS112 alone displayed marginal toxicity, the co-expression of both AS140 and AS112 enhanced the toxicity of AS140 [ 137 ].…”

Section: Snca Alternative Splicing and Its Rolementioning

confidence: 99%

Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies

Gámez-Valero

Beyer

2018

Genes

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The synuclein family is composed of three members, two of which, α- and β-synuclein, play a major role in the development of synucleinopathies, including Parkinson’s disease (PD) as most important movement disorder, dementia with Lewy bodies (DLB) as the second most frequent cause of dementia after Alzheimer’s disease and multiple system atrophy. Whereas abnormal oligomerization and fibrillation of α-synuclein are now well recognized as initial steps in the development of synucleinopathies, β-synuclein is thought to be a natural α-synuclein anti-aggregant. α-synuclein is encoded by the SNCA gene, and β-synuclein by SNCB. Both genes are homologous and undergo complex splicing events. On one hand, in-frame splicing of coding exons gives rise to at least three shorter transcripts, and the functional properties of the corresponding protein isoforms are different. Another type of alternative splicing is the alternative inclusion of at least four initial exons in the case of SNCA, and two in the case of SNCB. Finally, different lengths of 3’ untranslated regions have been also reported for both genes. SNCB only expresses in the brain, but some of the numerous SNCA transcripts are also brain-specific. With the present article, we aim to provide a systematic review of disease related changes in the differential expression of the various SNCA and SNCB transcript variants in brain, blood, and non-neuronal tissue of synucleinopathies, but especially PD and DLB as major neurodegenerative disorders.

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Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Cited by 13 publications

References 43 publications

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

Alpha-Synuclein Function and Dysfunction on Cellular Membranes

Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies

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