An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders

Longhena, Francesca; Faustini, Gaia; Brembati, Viviana; Pizzi, Marina; Benfenati, Fabio; Bellucci, Arianna

doi:10.1016/j.neubiorev.2021.08.011

Cited by 28 publications

(30 citation statements)

References 481 publications

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“…SV clustering is regulated by the synaptic vesicle-associated phosphoprotein, synapsin (De Camilli et al, 1983a;De Camilli et al, 1983b;Cesca et al, 2010;Longhena et al, 2021;Zhang and Augustine, 2021). A pioneering study at the lamprey reticulospinal (RS) synapse demonstrated that acute disruption of synapsin I with inhibitory antibodies caused a complete loss of the distal pool of SVs, leaving only docked SVs intact (Pieribone et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Fouke

Wegman

Weber

et al. 2021

Front. Cell Dev. Biol.

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Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.

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Section: Introductionmentioning

confidence: 99%

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Fouke

Wegman

Weber

et al. 2021

Front. Cell Dev. Biol.

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“…Cognitive abilities are contingent on a coordinated program of neurotransmitters transferred through presynaptic exocytosis, in which synapsin I (SYN1) plays a key role in regulating the reserve pool of synaptic vesicles in a phosphorylation-dependent manner at the presynaptic terminal [11,12]. In addition, SYN1 can modulate synaptic plasticity by altering the construction of synapses [13][14][15]. SYN1 is phosphorylated at distinct sites by different kinases, among which phospho-sites 4, 5 and 6 (Ser-62, Ser-67 and Ser-549) are phosphorylated by extracellular signal-regulated protein kinase (Erk), while phospho-site 7 (Ser-553) is regulated by cyclin-dependent protein kinases (Cdk5) [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

Zhi

Qiao²,

Zou

et al. 2021

CIMB

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With the wide application of microwave technology, concerns about its health impact have arisen. The signal transmission mode of the central nervous system and neurons make it particularly sensitive to electromagnetic exposure. It has been reported that abnormal release of amino acid neurotransmitters is mediated by alteration of p-SYN1 after microwave exposure, which results in cognitive dysfunction. As the phosphorylation of SYN1 is regulated by different kinases, in this study we explored the regulatory mechanisms of SYN1 fluctuations following microwave exposure and its subsequent effect on GABA release, aiming to provide clues on the mechanism of cognitive impairment caused by microwave exposure. In vivo studies with Timm and H&E staining were adopted and the results showed abnormality in synapse formation and neuronal structure, explaining the previously-described deficiency in cognitive ability caused by microwave exposure. The observed alterations in SYN1 level, combined with the results of earlier studies, indicate that SYN1 and its phosphorylation status (ser-553 and ser62/67) may play a role in the abnormal release of neurotransmitters. Thus, the role of Cdk5, the upstream kinase regulating the formation of p-SYN1 (ser-553), as well as that of MEK, the regulator of p-SYN1 (ser-62/67), were investigated both in vivo and in vitro. The results showed that Cdk5 was a negative regulator of p-SYN1 (ser-553) and that its up-regulation caused a decrease in GABA release by reducing p-SYN1 (ser-553). While further exploration still needed to elaborate the role of p-SYN1 (ser-62/67) for neurotransmitter release, MEK inhibition had was no impact on p-Erk or p-SYN1 (ser-62/67) after microwave exposure. In conclusion, the decrease of p-SYN1 (ser-553) may result in abnormalities in vesicular anchoring and GABA release, which is caused by increased Cdk5 regulated through Calpain-p25 pathway after 30 mW/cm2 microwave exposure. This study provided a potential new strategy for the prevention and treatment of microwave-induced cognitive dysfunction.

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confidence: 99%

“…Impairment of the synaptic vesicles machinery and neurotransmission is a characteristic feature of different movement disorders, including Parkinson's disease (PD), dystonia, and parkinsonism with dystonia. 1,2 Alpha-synuclein (α-Syn), a synaptic enriched protein member of the synucleins family, participates in the neuropathophysiology of PD. 3,4 Besides PD, its pathological aggregates characterize a wider group of neurodegenerative disorders defined as synucleinopathies.…”

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confidence: 99%

Alpha‐Synuclein is Involved in DYT1 Dystonia Striatal Synaptic Dysfunction

et al. 2022

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Background The neuronal protein alpha‐synuclein (α‐Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with α‐Syn. Both proteins act as molecular chaperones and control synaptic machinery. Despite such evidence, the role of α‐Syn in dystonia has never been investigated. Objective We explored whether α‐Syn and N‐ethylmaleimide sensitive fusion attachment protein receptor proteins (SNAREs), that are known to be modulated by α‐Syn, may be involved in DYT1 dystonia synaptic dysfunction. Methods We used electrophysiological and biochemical techniques to study synaptic alterations in the dorsal striatum of the Tor1a+/Δgag mouse model of DYT1 dystonia. Results In the Tor1a+/Δgag DYT1 mutant mice, we found a significant reduction of α‐Syn levels in whole striata, mainly involving glutamatergic corticostriatal terminals. Strikingly, the striatal levels of the vesicular SNARE VAMP‐2, a direct α‐Syn interactor, and of the transmembrane SNARE synaptosome‐associated protein 23 (SNAP‐23), that promotes glutamate synaptic vesicles release, were markedly decreased in mutant mice. Moreover, we detected an impairment of miniature glutamatergic postsynaptic currents (mEPSCs) recorded from striatal spiny neurons, in parallel with a decreased asynchronous release obtained by measuring quantal EPSCs (qEPSCs), which highlight a robust alteration in release probability. Finally, we also observed a significant reduction of TA striatal expression in α‐Syn null mice. Conclusions Our data demonstrate an unprecedented relationship between TA and α‐Syn, and reveal that α‐Syn and SNAREs alterations characterize the synaptic dysfunction underlying DYT1 dystonia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders

Cited by 28 publications

References 481 publications

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

Alpha‐Synuclein is Involved in DYT1 Dystonia Striatal Synaptic Dysfunction

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