Dataset Information

Decreased Vacuolar Ca2+ Storage and Disrupted Vesicle Trafficking Underlie Alpha-Synuclein-Induced Ca2+ Dysregulation in S. cerevisiae.

ABSTRACT: The yeast Saccharomyces cerevisiae is a powerful model to study the molecular mechanisms underlying ?-synuclein (?-syn) cytotoxicity. This is due to the high degree of conservation of cellular processes with higher eukaryotes and the fact that yeast does not endogenously express ?-synuclein. In this work, we focused specifically on the interplay between ?-syn and intracellular Ca2+ homeostasis. Using temperature-sensitive SEC4 mutants and deletion strains for the vacuolar Ca2+ transporters Pmc1 and Vcx1, together with aequorin-based Ca2+ recordings, we show that overexpression of ?-syn shifts the predominant temporal pattern of organellar Ca2+ release from a biphasic to a quasi-monophasic response. Fragmentation and vesiculation of vacuolar membranes in ?-syn expressing cells can account for the faster release of vacuolar Ca2+. ?-Syn further significantly reduced Ca2+ storage resulting in increased resting cytosolic Ca2+ levels. Overexpression of the vacuolar Ca2+ ATPase Pmc1 in wild-type cells prevented the ?-syn-induced increase in resting Ca2+ and was able to restore growth. We propose that ?-syn-induced disruptions in Ca2+ signaling might be an important step in initiating cell death.

SUBMITTER: Callewaert G

PROVIDER: S-EPMC7225347 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Decreased Vacuolar Ca2+ Storage and Disrupted Vesicle Trafficking Underlie Alpha-Synuclein-Induced Ca2+ Dysregulation in S. cerevisiae.

Callewaert Geert G D'hooge Petra P Ma Tien-Yang TY Del Vecchio Mara M Van Eyck Vincent V Franssens Vanessa V Winderickx Joris J

Frontiers in genetics 20200508

The yeast Saccharomyces cerevisiae is a powerful model to study the molecular mechanisms underlying α-synuclein (α-syn) cytotoxicity. This is due to the high degree of conservation of cellular processes with higher eukaryotes and the fact that yeast does not endogenously express α-synuclein. In this work, we focused specifically on the interplay between α-syn and intracellular Ca2+ homeostasis. Using temperature-sensitive SEC4 mutants and deletion strains for the vacuola ...[more]

PMID: 32457789

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Project description:α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called "cisternae." In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.

Project description:ObjectivesThe overall goal of the study was to identify functional and behavioral differences between individuals with higher tinnitus distress and individuals with lower tinnitus distress. Subsequent exploratory analyses were conducted to investigate the role physical activity may have on the observed results between high and low distress groups. The purpose of the experiment was to identify brain regions to be targeted in future intervention studies for tinnitus.DesignA total of 32 individuals with varying levels of tinnitus severity were recruited from the Urbana-Champaign area. Volunteers were divided into higher tinnitus distress (HD) and lower tinnitus distress (LD) groups. Note that these groups also significantly differed based on physical activity level and were subsequently stratified into higher and lower physical activity level subgroups for exploratory analysis. While in a functional magnetic resonance imaging (fMRI) scanner, subjects listened to affective sounds classified as pleasant, neutral or unpleasant from the International Affective Digital Sounds database.ResultsThe HD group recruited amygdala and parahippocampus to a greater extent than the LD group when listening to affective sounds. The LD group engaged frontal regions to a greater extent when listening to the affective stimuli compared to the HD group. Both higher physical activity level subgroups recruited more frontal regions, and both lower levels of physical activity subgroups recruited more limbic regions respectively.ConclusionIndividuals with lower tinnitus distress may utilize frontal regions to better control their emotional response to affective sounds. Our analysis also suggests physical activity may contribute to lower tinnitus severity and greater engagement of the frontal cortices. We suggest that future intervention studies focus on changes in the function of limbic and frontal regions when evaluating the efficacy of treatment. Additionally, we recommend further investigation concerning the impact of physical activity level on tinnitus distress.

Dataset Information

Decreased Vacuolar Ca2+ Storage and Disrupted Vesicle Trafficking Underlie Alpha-Synuclein-Induced Ca2+ Dysregulation in S. cerevisiae.

Publications

Decreased Vacuolar Ca<sup>2+</sup> Storage and Disrupted Vesicle Trafficking Underlie Alpha-Synuclein-Induced Ca<sup>2+</sup> Dysregulation in <i>S. cerevisiae</i>.

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