Synapsin Condensates Recruit alpha-Synuclein

Hoffmann, Christian; Sansevrino, Roberto; Morabito, Giuseppe; Logan, Chinyere; Vabulas, R. Martin; Ulusoy, Ayşe; Ganzella, Marcelo; Milovanović, Dragomir

doi:10.1016/j.jmb.2021.166961

Cited by 76 publications

(98 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to the classical view of SV clustering, synapsin cross-links SVs together in a "scaffold" of protein-protein interactions between synapsin and its binding partners, such as actin (Cesca et al, 2010;Zhang and Augustine, 2021). Recent in vitro studies, however, have instead proposed that synapsin clusters SVs via liquid-liquid phase separation (LLPS) through synapsin's intrinsically-disordered regions, by forming synapsin-SV condensates that are separated from the surrounding buffer (Milovanovic and De Camilli, 2017;Hoffmann et al, 2021;Park et al, 2021). A recent in vivo study at lamprey synapses supports this new model (Pechstein et al, 2020).…”

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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…It is interesting to note that genetic variants of the DNAJC family including CSPα/DNAJC5 have been associated with parkinsonism highlighting a functional pathway involved in the disease [ 135 ]. Another family of proteins acting at the synapse called synapsins interacts with α-syn and promotes α-syn functions at the synapse [ 136 , 137 ]. Synapsin III plays an important role as a cytosolic regulator of SV mobilisation [ 136 ].…”

Section: α-Synuclein Function In Exocytosismentioning

confidence: 99%

Alpha-Synuclein and Lipids: The Elephant in the Room?

Sarchione

Marchand

Taymans

et al. 2021

Cells

View full text Add to dashboard Cite

Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

show abstract

“…If the association of α-synuclein with SVs gives rise to oligomers as suggested by Burré and colleagues (Burré et al, 2014), a degree of cooperativity of binding may be expected. An alternative model suggests that α-synuclein is clustered together with synapsin and SVs in a liquid phase (Hoffmann et al, 2021), which would be governed by particular stoichiometries and modes of diffusion.…”

Section: A Quantitative Approach To α-Synuclein Dynamicsmentioning

confidence: 99%

A Quantitative Perspective of Alpha-Synuclein Dynamics – Why Numbers Matter

Specht

2021

Front. Synaptic Neurosci.

View full text Add to dashboard Cite

The function of synapses depends on spatially and temporally controlled molecular interactions between synaptic components that can be described in terms of copy numbers, binding affinities, and diffusion properties. To understand the functional role of a given synaptic protein, it is therefore crucial to quantitatively characterise its biophysical behaviour in its native cellular environment. Single molecule localisation microscopy (SMLM) is ideally suited to obtain quantitative information about synaptic proteins on the nanometre scale. Molecule counting of recombinant proteins tagged with genetically encoded fluorophores offers a means to determine their absolute copy numbers at synapses due to the known stoichiometry of the labelling. As a consequence of its high spatial precision, SMLM also yields accurate quantitative measurements of molecule concentrations. In addition, live imaging of fluorescently tagged proteins at synapses can reveal diffusion dynamics and local binding properties of behaving proteins under normal conditions or during pathological processes. In this perspective, it is argued that the detailed structural information provided by super-resolution imaging can be harnessed to gain new quantitative information about the organisation and dynamics of synaptic components in cellula. To illustrate this point, I discuss the concentration-dependent aggregation of α-synuclein in the axon and the concomitant changes in the dynamic equilibrium of α-synuclein at synapses in quantitative terms.

show abstract

Synapsin Condensates Recruit alpha-Synuclein

Cited by 76 publications

References 60 publications

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

Alpha-Synuclein and Lipids: The Elephant in the Room?

A Quantitative Perspective of Alpha-Synuclein Dynamics – Why Numbers Matter

Contact Info

Product

Resources

About