We study the molecular and biophysical mechanisms underlying vesicle trafficking in neurons and in particular in their axons and presynaptic nerve terminals.
Membrane vesicles filled with different cargos serve for communication between cells, intracellular compartments, and organelles. We study the molecular and biophysical mechanisms underlying vesicle trafficking, fusion, and endocytosis 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 autophagosome-lysosomal and protein degradation pathways. It is known, that effector synaptic proteins and scaffolding molecules, which are involved in coordination and targeting of the effector proteins and membrane lipids, control vesicle trafficking events in the nerve terminal.
Our recent studies show that mutations in genes encoding proteins involved in the synaptic and mitochondrial membrane trafficking, and genetic perturbations of transcription factors implicated in neurodegenerative diseases may cause the formation of pathological protein aggregates at synapses. Such aggregates resemble those observed in synucleinopathies and contain synuclein.
We are aiming at characterizing the signaling mechanisms that regulate the vesicle trafficking events, 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, Parkinsonfonden, Fernströms Foundation, and KI-NIH Cooperation Program.
Oleg Shupliakov – Professor, research group leader
Elena Sopova – Research assistant
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