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?-synuclein multimers cluster synaptic vesicles and attenuate recycling.

ABSTRACT: The normal functions and pathologic facets of the small presynaptic protein ?-synuclein (?-syn) are of exceptional interest. In previous studies, we found that ?-syn attenuates synaptic exo/endocytosis; however, underlying mechanisms remain unknown. More recent evidence suggests that ?-syn exists as metastable multimers and not solely as a natively unfolded monomer. However, conformations of ?-syn at synapses--its physiologic locale--are unclear, and potential implications of such higher-order conformations to synaptic function are unknown. Exploring ?-syn conformations and synaptic function in neurons, we found that ?-syn promptly organizes into physiological multimers at synapses. Furthermore, our experiments indicate that ?-syn multimers cluster synaptic vesicles and restrict their motility, suggesting a novel role for these higher-order structures. Supporting this, ?-syn mutations that disrupt multimerization also fail to restrict synaptic vesicle motility or attenuate exo/endocytosis. We propose a model in which ?-syn multimers cluster synaptic vesicles, restricting their trafficking and recycling, and consequently attenuate neurotransmitter release.

SUBMITTER: Wang L

PROVIDER: S-EPMC4190006 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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α-synuclein multimers cluster synaptic vesicles and attenuate recycling.

Wang Lina L Das Utpal U Scott David A DA Tang Yong Y McLean Pamela J PJ Roy Subhojit S

Current biology : CB 20140925 19

The normal functions and pathologic facets of the small presynaptic protein α-synuclein (α-syn) are of exceptional interest. In previous studies, we found that α-syn attenuates synaptic exo/endocytosis; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer. However, conformations of α-syn at synapses--its physiologic locale--are unclear, and potential implications of such higher-order c ...[more]

PMID: 25264250

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Project description:Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

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?-synuclein multimers cluster synaptic vesicles and attenuate recycling.

Publications

α-synuclein multimers cluster synaptic vesicles and attenuate recycling.

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