Stopping enzyme could launch two-pronged attack on Alzheimer's
Published on: 20 September 2019
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).
Research Areas
- Vesicular trafficking in neurons and neurosecretory cells
- Neuroexocytosis
- Neurodegenerative conditions
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.
Selected journal publications
Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic.
Bademosi, Adekunle T. , Steeves, James, Karunanithi, Shanker, Zalucki, Oressia H, Gormal, Rachel S, Liu, Shu, Lauwers, Elsa, Verstreken, Patrik, Anggono, Victor, Meunier, Frederic A and van Swinderen, Bruno (2018). Cell reports, 22 2: 427-440. doi:10.1016/j.celrep.2017.12.054
Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies. Polanco, Juan Carlos, Li, Chuanzhou, Bodea, Liviu-Gabriel, Martinez-Marmol, Ramon, Meunier, Frederic A and Götz, Jürgen (2017). Nature reviews. Neurology, 14 1: 22-40. doi:10.1038/nrneurol.2017.162
Visualizing endocytic recycling and trafficking in live neurons by subdiffractional tracking of internalized molecules.
Joensuu, Merja, Martinez-Marmol, Ramon, Padmanabhan, Pranesh, Glass, Nick R., Durisic, Nela, Pelekanos, Matthew, Mollazade, Mahdie, Balistreri, Giuseppe, Amor, Rumelo, Cooper-White, Justin J., Goodhill, Geoffrey J. and Meunier, Frederic A. (2017) Nature Protocols, 12 12:2590-2622. doi:10.1038/nprot.2017.116
The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals.
Vanhauwaert, Roeland, Kuenen, Sabine, Masius, Roy, Bademosi, Adekunle, Manetsberger, Julia, Schoovaerts, Nils, Bounti, Laura, Gontcharenko, Serguei, Swerts, Jef, Vilain, Sven, Picillo, Marina, Barone, Paolo, Munshi, Shashini T., de Vrij, Femke M. S., Kushner, Steven A., Gounko, Natalia V., Mandemakers, Wim, Bonifati, Vincenzo, Meunier, Frederic A., Soukup, Sandra‐Fausia and Verstreken, Patrik (2017)EMBO Journal, 36 10: 1392-1411. doi:10.15252/embj.201695773
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 Communications, 8 . 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 Biology, 215 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 Communications, 7 . 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 Biology, 214 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 Biology, 214 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 Biology, 22 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 Psychiatry, 20 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 Neuroscience, 35 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 Communications, 6 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 Neuroscience, 35 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 Reports, 9 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 Communications, 5 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 Biology, 200 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 Neuroscience, 33 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 Biology, 23 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 Communications, 2 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 Biology, 190 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 Journal, 29 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 Chemistry, 284 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 Neuroscience, 28 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 Proteomics, 6 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 America, 102 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 Medicine, 9 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 Journal, 21 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
Tau and ITS master regulator Fyn in Neurons
(2017–2019) NHMRC Project Grant
Understanding axonal fusion: an alternative mechanism to repair injured axons.
(2017–2019) NHMRC Project Grant
Unravelling a new fatty acid pathway involved in neuroexocytosis and memory
(2017–2019) NHMRC Project Grant
Unravelling the mechanism coupling synaptic activity with neurotrophin signaling in the nervous system
(2017–2019) NHMRC Project Grant
Unveiling the intra and intermolecular steps underpinning vesicular priming
(2017–2019) ARC Discovery Projects
Embryonic Animals and Tissue Culture
(2016–2017) CNGBio Corp
Unravelling the mechanism of vesicular docking in neurosecretory cells
(2015–2018) ARC Discovery Projects
Vesicular trafficking pathways underpinning neuronal secretion and survival
(2014–2018) NHMRC Research Fellowship (SRFB)
Prospective candidates should be highly motivated and have previous experience in neuroscience, microscopy and/or biophysics and engineering.
Project 1: Use of single molecule imaging to track botulinum neurotoxin interaction with the neuronal membrane
Project 2: Use of single molecule imaging to track epigenetic modifications elicited by synaptic plasticity associated with memory
Project 3: Use of single molecule imaging to uncover the change in presynaptic nanoscale organization occurring during neurotransmitter release (endocytosis)
Project 4: Use of single molecule imaging to uncover the change in presynaptic nanoscale organization occurring during neurotransmitter release (exocytosis)
Project 5: Use of single molecule imaging to uncover the change in Fyn and associated signalling cascade occurring during the development of Alzheimer’s disease
Project 6: Use of single molecule imaging to uncover the change in a-synuclein nanoscale organization in neurons associated with various disease-causing mutations
