Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins

Wilhelm, Benjamin G.; Mandad, Sunit; Truckenbrodt, Sven; Kröhnert, Katharina; Schäfer, Christina; Rammner, Burkhard; Koo, Seong Joo; Claßen, Gala A.; Krauß, Michael; Haucke, Volker; Urlaub, Henning; Rizzoli, Silvio O.

doi:10.1126/science.1252884

Cited by 688 publications

(752 citation statements)

References 47 publications

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“…The physiological concentration of α-synuclein in neuronal synapses is estimated to be about 50 μM (27,28), a concentration of protein that can be studied by NMR spectroscopy (27,(29)(30)(31)(32). We therefore used this technique to probe potential interactions between α-synuclein and squalamine in the absence of lipids and to characterize the displacement of the protein from lipid membranes by squalamine, as suggested by the CD experiments.…”

Section: Resultsmentioning

confidence: 99%

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

262

369

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The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

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Section: Resultsmentioning

confidence: 99%

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

262

369

View full text Add to dashboard Cite

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“…These lipids have the characteristic feature of a large polar head that can increase their solubility in aqueous solution (1-30 μM for GM1) (11,45,46). It is interesting in this regard that the presence of transmembrane and peripheral proteins in synaptic vesicles is also likely to modulate the efficiency of α-synuclein binding to the vesicles, and hence their capacity to enhance protein aggregation (38,47).…”

Section: Discussionmentioning

confidence: 99%

Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein

Galvagnion

Brown

Ouberaï

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

282

360

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Intracellular α-synuclein deposits, known as Lewy bodies, have been linked to a range of neurodegenerative disorders, including Parkinson's disease. α-Synuclein binds to synthetic and biological lipids, and this interaction has been shown to play a crucial role for both α-synuclein's native function, including synaptic plasticity, and the initiation of its aggregation. Here, we describe the interplay between the lipid properties and the lipid binding and aggregation propensity of α-synuclein. In particular, we have observed that the binding of α-synuclein to model membranes is much stronger when the latter is in the fluid rather than the gel phase, and that this binding induces a segregation of the lipids into protein-poor and protein-rich populations. In addition, α-synuclein was found to aggregate at detectable rates only when interacting with membranes composed of the most soluble lipids investigated here. Overall, our results show that the chemical properties of lipids determine whether or not the lipids can trigger the aggregation of α-synuclein, thus affecting the balance between functional and aberrant behavior of the protein.

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“…37 Comparison of synaptosomal proteins with proteins in undisturbed brain slices has shown that synaptic bouton protein composition is maintained in synaptosomes. 41 Demographic and neuropathologic data for the normal control, HPC, and AD cases are shown in Table 1. HPCs indicated substantial Ab and/or tau pathology but did not meet clinical criteria for dementia.…”

Section: Total In Situ Synaptic Ab Is Associated With Plaque Level Inmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins

Abstract: Fig. S6Tables S1 to S3 (as Excel files) Movie S1

Cited by 688 publications

References 47 publications

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

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