Synucleins Are Developmentally Expressed, and α-Synuclein Regulates the Size of the Presynaptic Vesicular Pool in Primary Hippocampal Neurons

By D. Murphy, S. Rueter, John Q. Trojanowski, V. Lee. Journal of Neuroscience, 2000

915 citations recorded by the source corpus.

α-, β-, and γ-Synuclein, a novel family of neuronal proteins, has become the focus of research interest because α-synuclein has been increasingly implicated in the pathogenesis of Parkinson's and Alzheimer's disease. However, the normal functions of the synucleins are still unknown. For this reason, we characterized α-, β-, and γ-synuclein expression in primary hippocampal neuronal cultures and showed that the onset of α- and β-synuclein expression was delayed after synaptic development, suggesting that these synucleins may not be essential for synapse formation. In mature cultured primary neurons, α- and β-synuclein colocalized almost exclusively with synaptophysin in the presynaptic terminal, whereas little γ-synuclein was expressed at all. To assess the function of α-synuclein, we suppressed expression of this protein with antisense oligonucleotide technology. Morphometric ultrastructural analysis of the α-synuclein antisense oligonucleotide-treated cultures revealed a significant reduction in the distal pool of synaptic vesicles. These data suggest that one function of α-synuclein may be to regulate the size of distinct pools of synaptic vesicles in mature neurons.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/2ba1e5e549242040cc3d738ba641c336ec69da9e

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Citations in the corpus

Synaptic Vesicle Depletion Correlates with Attenuated Synaptic Responses to Prolonged Repetitive Stimulation in Mice Lacking α-Synuclein (2002, methodology): “Murphy et al. (2000) performed an ultrastructural study of synaptic vesicles in fetal rat hippocampal cultures in which -synuclein expression was reduced by 50% using antisense oligonucleotides.”
Molecular pathophysiology of Parkinson's disease. (2005, background): “Furthermore, in cultured cells α-synuclein can regulate lipid metabolism by protecting lipid droplets from hydrolysis (Cole et al. 2002) and can regulate the size of presynaptic vesicular pools (Murphy et al. 2000).”
Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction (2023, background): “The lack of physiological α-syn has been associated with a reduction in the number of synaptic vesicles of distal pools [28], whereas its overexpression has been shown to increase the number of vesicles docked to the membranes [29].”
Helix periodicity, topology, and dynamics of membrane‐associated α‐Synuclein (2005, background): “Evidence that aS controls synaptic strength comes from neuronal cell line and knockout mouse models (Abeliovich et al. 2000; Murphy et al. 2000; Cabin et al. 2002; Schluter et al. 2003) that display impaired synaptic response to repetitive stimuli and alterations in the number of reserve pool vesicl”
A Role for α-Synuclein in the Regulation of Dopamine Biosynthesis (2002, background): “-Synuclein and 14-3-3 are both enriched in the cytoplasm of nerve terminals (Maroteaux et al., 1988; Irizarry et al., 1996; Broadie et al., 1997; Withers et al., 1997; Murphy et al., 2000), the same compartment that contains TH (Pickel et al.”
Parkinson's Disease Mechanisms and Models (2003, neutral): “Parkincampal glutamatergic neurons (Murphy et al., 2000).”
α-Synuclein in Parkinson's disease. (2012, background): “…is induced during neuronal development, following determination of neuronal phenotype and establishment of synaptic connections, and lags behind the induction of proteins involved in synaptic structure (Withers et al. 1997; Kholodilov et al. 1999; Murphy et al. 2000; Rideout et al. 2003).”
Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death (2011, neutral): “In PBS-treated control neurons, there was an increase in αsyn levels by DIV10 as demonstrated previously (Murphy et al., 2000).”