We study the molecular and biophysical mechanisms underlying and regulating vesicle trafficking in neurons and in particular in their axons and presynaptic nerve terminals. Our current interest is in the molecular mechanisms, which link the synaptic vesicle cycle with the onset of neurodegenerative diseases and primerily under conditions that lead to α-synuclein-related pathologies observed in Parkinson’s disease, as well as in several diseases referred to as synucleinopathies.
Liquid-liquid phase separation in cells has emerged as a common principle for the organization of membrane-less compartments. In nerve terminals in the central nervous system, liquid-liquid phase separation has been implicated in the organization or assembly of several functional compartments. We are aiming at characterizing the signaling mechanisms that regulate the liquid-liquid phase transitions in the synaptic vesicle cycle, mitochondrial functions, and degradation pathways at nerve terminals to clarify how do they become affected at the early stages of neurodegenerative diseases and which molecular steps lead to protein aggregate formation. To address our goals we use several model systems such as giant reticular spinal axon in lamprey, Drosophila neuromuscular junction, and mammalian neurons, in combination with molecular biology, genetics, cellular imaging techniques, and intracellular recordings.
We believe that our experiments will pave the way for the identification of therapeutic targets for treatments of neurodegenerative disorders.
Our studies are supported by Vetenskaprådet (Swedish Research Council), Hjärnfonden and Parkinsonfonden.
Clathrin-mediated endocytosis cooperates with bulk endocytosis to generate vesicles.
Arpino G, Somasundaram A, Shin W, Ge L, Villareal S, Chan CY, Ashery U, Shupliakov O, Taraska JW, Wu LG
iScience 2022 Feb;25(2):103809
α-Synuclein in the Synaptic Vesicle Liquid Phase: Active Player or Passive Bystander?
Brodin L, Milovanovic D, Rizzoli SO, Shupliakov O
Front Mol Biosci 2022 ;9():891508
Preformed Ω-profile closure and kiss-and-run mediate endocytosis and diverse endocytic modes in neuroendocrine chromaffin cells.
Shin W, Wei L, Arpino G, Ge L, Guo X, Chan CY, Hamid E, Shupliakov O, Bleck CKE, Wu LG
Neuron 2021 Oct;109(19):3119-3134.e5
Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
Filograna R, Lee S, Tiklová K, Mennuni M, Jonsson V, Ringnér M, Gillberg L, Sopova E, Shupliakov O, Koolmeister C, Olson L, Perlmann T, Larsson NG
PLoS Genet 2021 Sep;17(9):e1009822
Vesicle Clustering in a Living Synapse Depends on a Synapsin Region that Mediates Phase Separation.
Pechstein A, Tomilin N, Fredrich K, Vorontsova O, Sopova E, Evergren E, et al
Cell Rep 2020 Feb;30(8):2594-2602.e3
Vesicle Shrinking and Enlargement Play Opposing Roles in the Release of Exocytotic Contents.
Shin W, Arpino G, Thiyagarajan S, Su R, Ge L, McDargh Z, et al
Cell Rep 2020 Jan;30(2):421-431.e7
Retromer in Synaptic Function and Pathology.
Brodin L, Shupliakov O
Front Synaptic Neurosci 2018 ;10():37
Intersectin associates with synapsin and regulates its nanoscale localization and function.
Gerth F, Jäpel M, Pechstein A, Kochlamazashvili G, Lehmann M, Puchkov D, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 11;114(45):12057-12062
Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane.
Wen PJ, Grenklo S, Arpino G, Tan X, Liao HS, Heureaux J, et al
Nat Commun 2016 08;7():12604
Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin-proteasome mediated mechanism.
Mitroi DN, Deutschmann AU, Raucamp M, Karunakaran I, Glebov K, Hans M, et al
Sci Rep 2016 11;6():37064
An Endocytic Scaffolding Protein together with Synapsin Regulates Synaptic Vesicle Clustering in the Drosophila Neuromuscular Junction.
Winther ÅM, Vorontsova O, Rees KA, Näreoja T, Sopova E, Jiao W, et al
J. Neurosci. 2015 Nov;35(44):14756-70
Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease.
Laguna A, Schintu N, Nobre A, Alvarsson A, Volakakis N, Jacobsen JK, et al
Nat. Neurosci. 2015 Jun;18(6):826-35