Single Molecule Neuroscience Laboratory

About

The overall goal of our research is to determine how brain cells communicate and survive in health and disease. Our lab focuses on the molecular events that govern vesicular trafficking within presynaptic nerve terminals and neurosecretory cells. Our discoveries have led to a deep understanding of how secretory vesicles interact with the cortical actin network prior to fusing with the plasma membrane to release the neurotransmitter. We have identified a critical role of the phospholipid phosphatidylinositol (4,5) bisphosphate in coordinating the actin-mediated recruitment of secretory vesicles to the plasma membrane. This active mechanism allows secretory vesicles to dock with the plasma membrane prior to fusion and is controlled by the effector cdc42. We have recently uncovered a new mechanism that allows secretory vesicles to be recruited on the cortical actin network.

We demonstrated that the protein Munc18-1 was responsible for the transport of syntaxin-1 to the plasma membrane. This novel trafficking/chaperoning pathway underpins neurotransmission, as secretory vesicles rely on the zippering of SNARE proteins such as syntaxin-1 to undergo fusion with the plasma membrane. Following exocytosis, the process of endocytosis is required for neurons to replenish their pools of synaptic vesicles by pinching off vesicles from the plasma membrane. We have identified a novel mechanism by which dynamin and actin coordinate a series of membrane events that culminate in the formation of bulk endosomes from which new synaptic vesicles emanate at the neuromuscular junction. We have also demonstrated that dynamin is a valid prophylactic target against infection and intoxication. 

As part of the Clem Jones Centre for Ageing Dementia Research, the Meunier laboratory has capitalised on the recent acquisition of several super-resolution microscopes to uncover how neurotrophic factors are packaged in nanodomains of presynaptic terminals and then channelled back to the cell body.

Our lab is keen on taking on highly motivated and high achieving students (Honours and PhD).

Contact

  @MeunierLab

  +61 7 334 66373

  f.meunier@uq.edu.au


Group Publications

Research Areas

  • Vesicular trafficking in neurons and neurosecretory cells
  • Neuroexocytosis
  • Neurodegenerative conditions

Group Leader


Research Members

  • Dr Merja Joensuu

    Postdoctoral Research Fellow
    Queensland Brain Institute
  • Dr Ramon Martinez-Marmol

    Postdoctoral Research Fellow
    Queensland Brain Institute
  • Dr Isabel Morrow

    Casual Research Assistant AIBN
    Australian Institute for Bioengineering and Nanotechnology
    Casual Research Assistant
    Queensland Brain Institute

Students


Support Staff


Super-resolution microscopy at the site of neuronal communication

QBI houses the Advanced Microimaging and Analysis Facility, which contains state-of-the art microscopes. Our lab has been instrumental in the inclusion of several super-resolution microscopes, through successive ARC LIEF grants. This has allowed us to probe the nanoscopic environment of neurons and neurosecretory cells undergoing communication. Our most recent publications have used super-resolution microscopy extensively.  

Deciphering the intra- and intermolecular steps via which prepare secretory vesicles for fusion is key to understanding neuronal and hormonal communication. We demonstrated that Munc18-1 and syntaxin-1A and are organised in nanodomains on the plasma membrane of neurons and neurosecretory cells that control SNARE-dependent neuroexocytosis through lateral trapping in these nanoclusters. In Bademosi et al. 2017 (Nature Communications), we combined super-resolution with opto- and thermogenetic neuronal stimulation in living neurons in the fruit fly.  We were able to characterise the changes in mobility of the tSNARE syntaxin1a and how they regulate neurotransmitter release. In Kasula et al. 2016 (Journal of Cell Biology) we found that the Munc18-1 domain 3a hinge-loop controls syntaxin-1A engagement into the SNARE complex during priming. 

We also developed a new technique sdTIM, Subdiffractional tracking of internalised molecules, to be able to visualise small synaptic vesicles in living hippocampal nerve terminals (Joensuu et al. 2016 Journal of Cell Biology).  This super-resolution technique was able to capture, and subsequently analyse, the dynamics of thousands of individual synaptic vesicle trajectories, to uncover the dynamics of synaptic vesicle pool mobility.  It revealed diffusive and transport states of synaptic vesicles in resting and stimulated conditions. Our aim is to apply sdTIM to study the mechanism of neuronal communication under disease conditions in future studies.  
 

Munc18 and synucleopathies

Because of the importance of Munc18-1 in vesicle fusion, human mutations are linked to epilepsy and other neurological symptoms. Recent genetic studies in humans have uncovered a variety of mutations in Munc18 that lead to EIEE (early infantile epileptic encephalopathy), a severe and often fatal developmental condition with no treatment, and little knowledge of the underlying cause. We showed that the human disease- linked mutation C180Y, which is unstable at body temperature, leads to the formation of intracellular aggregates (Martin et al. 2014 Cell Reports). In a follow up study, we revealed that both C180Y and other human EIEE-linked missense mutations controlled the aggregation of α-synuclein, in a similar fashion to Parkinson's disease pathology (Chai et al. 2016 Journal of Cell Biology). This provides the first evidence for a communal mode of action between an epileptic syndrome and neurodegenerative synucleopathies. This is an ongoing field of research in our laboratory.
 


In vivo single-molecule imaging of syntaxin1A reveals polyphosphoinositide- and activity-dependent trapping in presynaptic nanoclusters
Bademosi, Adekunle T., Lauwers, Elsa, Padmanabhan, Pranesh, Odierna, Lorenzo, Chai, Ye Jin, Papadopulos, Andreas, Goodhill, Geoffrey J., Verstreken, Patrik, Van Swinderen, Bruno and Meunier, Frederic A. (2017) Nature Communications8 . doi:10.1038/ncomms13660

Subdiffractional tracking of internalized molecules reveals heterogeneous motion states of synaptic vesicles
Joensuu, Merja, Padmanabhan, Pranesh, Durisic, Nela, Bademosi, Adekunle T. D., Cooper-Williams, Elizabeth, Morrow, Isabel C., Harper, Callista B., Jung, WooRam, Parton, Robert G., Goodhill, Geoffrey J., Papadopulos, Andreas and Meunier, Frederic A. (2016)  Journal of Cell Biology215 2: 277-292. doi:10.1083/jcb.201604001

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB
Wang, Tong, Martin, Sally, Nguyen, Tam H., Harper, Callista B., Gormal, Rachel S., Martinez-Marmol, Ramon, Karunanithi, Shanker, Coulson, Elizabeth J., Glass, Nick R., Cooper-White, Justin J., Van Swinderen, Bruno and Meunier, Frederic A. (2016)  Nature Communications7 . doi:10.1038/ncomms12976

The Munc18-1 domain 3a hinge-loop controls syntaxin-1A nanodomain assembly and engagement with the SNARE complex during secretory vesicle priming
Kasula, Ravikiran, Chai, Ye Jin, Bademosi, Adekunle T., Harper, Callista B., Gormal, Rachel S., Morrow, Isabel C., Hosy, Eric, Collins, Brett M., Choquet, Daniel, Papadopulos, Andreas and Meunier, Frederic A. (2016)  The Journal of Cell Biology214 7: 847-858. doi:10.1083/jcb.201508118

Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation
Chai, Ye Jin, Sierecki, Emma, Tomatis, Vanesa M., Gormal, Rachel S., Giles, Nichole, Morrow, Isabel C., Xia, Di, Götz, Jürgen, Parton, Robert G., Collins, Brett M., Gambin, Yann and Meunier, Frédéric A. (2016) The Journal of Cell Biology214 6: 705-718. doi:10.1083/jcb.201512016

Profiling of free fatty acids using stable isotope tagging uncovers a role for saturated fatty acids in neuroexocytosis
Narayana, Vinod K., Tomatis, Vanesa M., Wang, Tong, Kvaskoff, David and Meunier, Frederic A. (2015) Chemistry and Biology22 11: 1552-1561. doi:10.1016/j.chembiol.2015.09.010

Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release
Jackson, J., Papadopulos, A., Meunier, F. A., McCluskey, A., Robinson, P. J. and Keating, D. J. (2015)  Molecular Psychiatry20 7: 810-819. doi:10.1038/mp.2015.56

Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A
Wang, Tong, Martin, Sally, Papadopulos, Andreas, Harper, Callista B., Mavlyutov, Timur A., Niranjan, Dhevahi, Glass, Nick R., Cooper-White, Justin J., Sibarita, Jean-Baptiste, Choquet, Daniel, Davletov, Bazbek and Meunier, Frederic A. (2015) Journal of Neuroscience35 15: 6179-6194. doi:10.1523/JNEUROSCI.3757-14.2015

Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking
Papadopulos, Andreas, Gomez, Guillermo A., Martin, Sally, Jackson, Jade, Gormal, Rachel S., Keating, Damien J., Yap, Alpha S. and Meunier, Frederic A. (2015) Nature Communications6 6297: 1-11. doi:10.1038/ncomms7297

An acto-myosin II constricting ring initiates the fission of activity-dependent bulk endosomes in neurosecretory cells
Gormal, Rachel S, Nguyen, Tam H, Martin, Sally, Papadopulos, Andreas and Meunier, Frederic A (2015)  Journal of Neuroscience35 4: 1380-1389. doi:10.1523/JNEUROSCI.3228-14.2015

Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis
Martin, Sally, Papadopulos, Andreas, Tomatis, Vanesa M., Sierecki, Emma, Malintan, Nancy T., Gormal, Rachel S., Giles, Nichole, Johnston, Wayne A., Alexandrov, Kirill, Gambin, Yann, Collins, Brett M. and Meunier, Frederic A. (2014) Cell Reports9 1: 206-218. doi:10.1016/j.celrep.2014.08.059

PI3K delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
Low, Pei Ching, Manzanero, Silvia, Mohannak, Nika, Narayana, Vinod K., Nguyen, Tam H., Kvaskoff, David, Brennan, Faith H., Ruitenberg, Marc J., Gelderblom, Mathias, Magnus, Tim, Kim, Hyun Ah, Broughton, Brad R. S., Sobey, Christopher G., Vanhaesebroeck, Bart, Stow, Jennifer L., Arumugam, Thiruma V. and Meunier, Frédéric A. (2014) Nature Communications5 3450: 1-12. doi:10.1038/ncomms4450

Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin
Tomatis, Vanesa M., Papadopulos, Andreas, Malintan, Nancy T., Martin, Sally, Wallis, Tristan, Gormal, Rachel S., Kendrick-Jones, John, Buss, Folma and Meunier, Frederic A. (2013) Journal of Cell Biology200 3: 301-320. doi:10.1083/jcb.201204092

Secretagogue stimulation of neurosecretory cells elicits filopodial extensions uncovering new functional release sites
Papadopulos, Andreas, Martin, Sally, Tomatis, Vanesa M., Gormal, Rachel S. and Meunier, Frederic A. (2013) Secretagogue stimulation of neurosecretory cells elicits filopodial extensions uncovering new functional release sites.Journal of Neuroscience33 49: 19143-19153. doi:10.1523/JNEUROSCI.2634-13.2013

Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors
Harper, Callista B., Popoff, Michel R., McCluskey, Adam, Robinson, Phillip J. and Meunier, Frederic A. (2013) Trends in Cell Biology23 2: 90-101. doi:10.1016/j.tcb.2012.10.007

Phosphatidylinositol(4,5)bisphosphate coordinates actin-mediated mobilization and translocation of secretory vesicles to the plasma membrane of chromaffin cells
Wen, Peter J., Osborne, Shona L., Zanin, Mark, Low, Pei Ching, Wang, Hai-Tao A., Schoenwaelder, Simone M., Jackson, Shaun P., Wedlich-Soldner, Roland, Vanhaesebroeck, Bart, Keating, Damien J. and Meunier, Frederic A. (2011)  Nature Communications2 1: 491.1-491.11. doi:10.1038/ncomms1500

Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion
Low, Pei Ching, Misaki, Ryo, Schroder, Kate, Stanley, Amanda C., Sweet, Matthew J., Teasdale, Rohan D., Vanhaesebroeck, Bart, Meunier, Frédéric A., Taguchi, Tomohiko and Stow, Jennifer L. (2010)  Journal of Cell Biology190 6: 1053-1065. doi:10.1083/jcb.201001028

Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella
Kerr, Markus C., Wang, Jack T. H., Castro, Natalie A., Hamilton, Nicholas A., Town, Liam, Brown, Darren L., Meunier, Frederic A., Brown, Nat F., Stow, Jennifer L. and Teasdale, Rohan D. (2010)  EMBO Journal29 8: 1331-1347. doi:10.1038/emboj.2010.28

Abrogating Munc18-1 SNARE complex interaction has limited impact on exocytosis in PC12 cells
Malintan, Nancy, Nguyen, Tam H, Han, Liping, Latham, Catherine F., Osborne, Shona L., Wen, Peter, Lim, Siew, Joo, Tiffany, Sugita, Shuzo, Collins, Brett M. and Meunier, Frederic A. (2009) The Journal of Biological Chemistry284 32: 21637-21646. doi:10.1074/jbc.M109.013508

p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate
Coulson, E. J., May, L. M., Osborne, S. L., Reid, K., Underwood, C. K., Meunier, F. A., Bartlett, P. F. and Sah, P. (2008)  Journal of Neuroscience28 1: 315-324. doi:10.1523/JNEUROSCI.2699-07.2008

Identification of secretory granule phosphatidylinositol 4,5-bisphosphateinteracting proteins using an affinity pulldown strategy
Osborne, SL, Wallis, TP, Jimenez, JL, Gorman, JJ and Meunier, FA (2007) Molecular & Cellular Proteomics6 7: 1158-1169. doi:10.1074/mcp.M600430-MCP200

Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the alpha-conotoxin MII
Clark, R. J., Fischer, H., Dempster, L., Daly, N. L., Rosengren, K. J., Nevin, S. T., Meunier, F. A., Adams, D. J. and Craik, D. J. (2005)  Proceedings of The National Academy of Sciences of The United States of America102 39: 13767-13772. doi:10.1073/pnas.0504613102

Getting muscles moving again after botulinum toxin: novel therapeutic challenges
Foran, PG, Davletov, B and Meunier, FA (2003) Trends In Molecular Medicine9 7: 291-299. doi:10.1016/S1471-4914(03)00113-8

Glycerotoxin from Glycera convoluta stimulates neurosecretion by up-regulating N-type Ca2+ channel activity
Meunier, Frédéric A., Feng, Zhong-Ping, Molgó, Jordi, Zamponi, Gerald W. and Schiavo, Giampietro (2002) The EMBO Journal21 24: 6733-6743. doi:10.1093/emboj/cdf677

 

The University of Queensland

 

  • Professor Elizabeth Coulson, QBI
  • Professor Jürgen Götz, QBI
  • Associate Professor Massimo Hilliard, QBI
  • Associate Professor Bruno van Swinderen, QBI
  • Associate Professor Brett Collins, IMB
  • Professor Jenny Stow, IMB
  • Professor Robert Parton, IMB
  • Associate Professor Rohan Teasdale, IMB
  • Professor Alpha Yap, IMB
  • Professor Justin Cooper-White, AIBN
  • Associate Professor Peter Noakes, SBMS
  • Dr. Marc Ruitenberg, SBMS

National

  • Dr. Thomas Fath - Faculty of Medicine, University of New South Wales
  • Professor Phil Robinson - Children's Medical Research Institute (CMRI)
  • Professor Adam McCluskey - School of Environmental and Life Sciences, University of Newcastle
  • Associate Professor Damien Keating - School of Medicine, Flinders University
  • Dr. Yann Gambin - European Molecular Biology Laboratory Australia (EMBL), University of New South Wales.
  • Dr. Emma Siereki - School of Medical Science, University of New South Wales.

International

  • Professor Daniel Choquet - Interdisciplinary Institute for Neuroscience, Bordeaux, France.
  • Dr. Giuseppe Balistreri - Department of Biosciences University of Helsinki, Finland.
  • Dr. David Kvaskoff - Centre for Biochemistry, University of Heidelberg, Germany.
  • Professor Michel R Popoff - Unit for Anaerobic Bacteria and Toxins, Institute Pasteur, Paris, France.
  • Professor Jianyuan Sun - The Institute of Biophysics, The Chinese Academy of Science, Beijing, China.
  • Professor Shuzo Sugita - Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto, Canada.
  • Professor Britta Brügger - Centre for Biochemistry, University of Heidelberg, Germany.
  • Professor Bazbek Davletov - Department of Biomedical Science, The University of Sheffield, England