Protein trafficking in disease

The highly co-ordinated movement of the thousands of distinct membrane proteins between the cell surface and intracellular compartments is a critical factor in health and disease. This movement controls the organisation of cells in tissues and communication between cells and their environment. The success of this process depends on the regulated sorting and trafficking of proteins within the highly dynamic endosomal compartments of the cell in processes that are emerging as important drivers of neurodegenerative disease, cancer and metabolic pathologies. An understanding of how endosomal traffic is regulated, and how lysosomal traffic and degradation are modulated, is critical for providing insights into disease and devising new therapeutic approaches.

Retromer – A master regulator of endosome protein trafficking

EndsomesFidelity of transport through the endosomal system requires mechanisms that precisely sort cargoes for delivery to a range of different destinations. This is achieved by cargo engaging specific sorting machinery that is responsible for their accumulation into tubules that then undergo scission to generate endosome-transport carriers (ETCs). Once formed, these carrier vesicles engage the machinery at the target membrane, resulting in cargo delivery to the specific membrane, e.g. plasma membrane. Retromer has been identified to have a central role in this process and it is the spatial and temporal coordination of the interaction between Retromer and associated proteins that determines the properties of the individual endosome-transport carriers formed. We are currently investigating the contribution each of the variant Retromer complexes has on the formation of the distinct endosome-transport carrier types and to the sorting of a range of cargo actively transported by these vesicles.

Retromer’s role in neurodegeneration

Our research into defining the composition of a mammalian endosomal protein complex, termed Retromer, has made major contributions to its recent emergence as a central, critical regulator of early endosome protein trafficking. Recently, pathogenetic mutations within a Retromer subunit, Vps35, have been directly associated with causing late onset Parkinson’s disease. More broadly, endosomes are emerging to have a central role in the pathobiology of neurodegenerative diseases, including Alzheimer’s & Parkinson’s diseases.

In ongoing studies, we have found that disruption of known Retromer components contributes to the cellular pathology phenotypes associated with Parkinson’s disease (PD). It is proposed that perturbing the Retromer-mediated formation of endosome to trans-Golgi Network (TGN) transport carriers directly underpins the manifestation of cellular phenotypes, such as alpha-synuclein aggregation, that lead to the development of PD. Significantly, preliminary studies have revealed that the pharmacological enhancement of Retromer function is able to reduce the severity of PD-associated cellular phenotypes, establishing Retromer as a potential therapeutic target. As Retromer has also been implicated in Alzheimer’s disease, the Group’s research is relevant to multiple, progressive, neurological disorders that are the most common causes of dementia.

Retromer-dependent protein trafficking and adipocyte biology

Retromer-dependent protein trafficking and adipocyte biologyAdipose tissue, commonly referred to as fat, influences the function of nearly all other organ systems through secretion of a diverse range of metabolites and peptide hormones. In a nutrient-rich or fed state, high levels of insulin bind to its receptor on adipocytes and the resulting cell signaling events cause the translocation of GLUT4-specialised vesicles (GSV) to the plasma membrane. This results in an increased glucose uptake via the GLUT4 transporter. The formation of GSVs within adipocytes represents an important part of this interconnected metabolic system and is critical for its regulation. Using a series of novel cell line and mouse models, we are examining the contribution Retromer-dependent endosome protein sorting and formation of endosome-transport carriers has on the generation of GSVs in adipocytes and its impact on adipocyte biology within whole animal models.

Defining the role host cell membrane trafficking pathways play in pathogen infection

Defining the role host cell membrane trafficking pathways play in pathogen infectionIn order to survive within the host cell, pathogens pirate the host cell’s membrane trafficking pathways to engineer intracellular niches, called inclusions. Using established molecular tools, in combination with sophisticated live-cell imaging technology, we will examine the membrane trafficking pathways hijacked by the pathogens. Our current research focuses on Salmonella typhimurium, a leading cause of human gastroenteritis, and Chlamydiae, the most prevalent cause of sexually transmitted disease.

  • Kerr MC, Gomez GA, Ferguson C, Tanzer MC, Murphy JM, Yap AS, Parton RG, Huston WM, Teasdale, R.D. Laser-mediated rupture of chlamydial inclusions triggers pathogen egress and host cell necrosis. Nature Communications (2017) 8 14729.
  •  Yang Z, Hong LK, Follett J, Wabitsch M, Hamilton NA, Collins BM, Bugarcic A, Teasdale, R.D. Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation. FASEB Journal (2016) 30 1037 – 1050.
  •  Follett J, Bugarcic A, Yang Z, Ariotti N, Norwood SJ, Collins BM, Parton RG, Teasdale, R.D. Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation. Journal of Biological Chemistry (2016) 291 18283 – 18298.
  •  Ariotti N, Hall TE, Rae J, Ferguson C, McMahon KA, Martel N, Webb RE, Webb RI, Teasdale, R.D., Parton RG. Modular Detection of GFP-Labeled Proteins for Rapid Screening by Electron Microscopy in Cells and Organisms. Developmental Cell (2015) 35 513 – 525.
  •  Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O, Tay S, Zhe Y, Wood SA, Mellick GD, Silburn PA, Collins BM, Bugarcic A, Teasdale, R.D. The Vps35 D620N Mutation Linked to Parkinson's Disease Disrupts the Cargo Sorting Function of Retromer. Traffic (2014) 15 230 – 244.
  •  Kerr M., Teasdale, R.D. Live imaging of endosome dynamics. Seminars In Cell and Developmental Biology (2014) 31 11 – 19.
  •  Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY, Larock CN, Davies MR, Schulz BL, Nizet V, Teasdale, R.D., Walker MJ. The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe (2013) 14 675 – 682.
  •  Teasdale, R.D. and Collins, B.C. Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease. Biochemistry Journal (2012) 441 39 – 59.
  •  Bugarcic A., Zhe Y., Kerr M.C., Griffin J., Collins B.M., and Teasdale, R.D. Vps26A and Vps26B Subunits Define Distinct Retromer Complexes. Traffic (2011) 12 1759 – 1773.
  •  Kerr M.C., Wang, J.T.H., Castro, N., Hamilton, N.A., Town, L., Brown, D.L., Meunier, F.A., Brown, N.F., Stow, J.L. and Teasdale, R.D.Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella. The EMBO Journal (2010) 8 295 1331 – 1347.
  •  Wang J.T., Kerr M.C., Karunaratne S., Jeanes A., Yap A.S., and Teasdale, R.D. The SNX-PX-BAR family in macropinocytosis: the regulation of macropinosome formation by SNX-PX-BAR proteins. PLoS One (2010) 5 e13763 -.
  •  Kerr M.C., and Teasdale, R.D. Defining macropinocytosis. Traffic (2009) 10 364 – 371.
  •  Sprenger, J., Fink, J.L., Karunaratne, S., Hanson, K., Hamilton, N., and Teasdale, R.D. LOCATE: A Mammalian Protein Subcellular Localization Database. Nucleic Acids Research (2008) 36 D230 - D233.
  •  Fink, J.L., Karunaratne, S., Mittal, A., Gardiner, D., Hamilton, N., Mahony,D., Kai, C., Suzuki, H., Hayashizaki, Y. and Teasdale, R.D. Towards defining the nuclear proteome. Genome Biology (2008) 9 R15 -.
  •  Kerr, M.C., Bennetts, J.C., Simpson, F., Thomas, E.C., Flegg, C., Gleeson, P.A, Wicking, C., and Teasdale, R.D. A Novel Mammalian Retromer Component, Vps26B. Traffic (2005) 6 991 – 1001.
  •  Teasdale, R.D., Loci, D., Karlsson, L. and Gleeson, P.A. A large family of endosomal localised proteins related to sorting nexin 1. Biochemical Journal (2001) 358 7 – 16.

To view the full publications, visit the links below:

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Past members

This group has had multiple previous lab members that have contributed to current and past research.

Dr David Liebl (Post-doctoral scientist, 2010-2014) -Electron Microscopy Suite Manager – Institute of Medical Biology, Singapore

Dr Andrea Bugarcic (Post-doctoral scientist, 2008-2015) – Associate Program Leader – Biosciences, Endeavour College of Natural Health

Dr Lynn Fink (Post-doctoral scientist, 2004-2008) – Group Leader, Diamantina Institute, The University of Queensland

Dr Nick Hamilton (Post-doctoral scientist, 2005-2008) – Group Leader - Institute Bio-Mathematician/IMB, The University of Queensland

A/Prof Brett Collins (NHMRC CDA, 2006-2007) – Group Leader, Institute for Molecular Bioscience, The University of Queensland

Past PhD students

This group has had multiple previous PHD students that are now employed in academia or research and development.

Dr Wei Xuan Teo (PhD Student, 2012-2016) – Research Fellow, Department of Anatomy, National University of Singapore. 

Dr Jordan Follett (PhD Student, 2012-2016) – Post-doctoral Scientist, Dr Matthew Farrer Group, Center for Applied Neurogenetics, The University of British Columbia 

Dr Xiaying Qi (PhD Student, 2011-2015) - Post-doctoral Scientist, The University of Queensland. 

Dr Jack Wang (PhD Student, 2007-2010) - Lecturer, School of Chemistry and Molecular Biosciences, The University of Queensland 

Dr Josephine Springer (PhD Student, 2007-2010) – Currently employed at SmartNet Presence and Information Professionals. 

Dr Melissa Davis (PhD Student, 2003-2007) - Group Leader Walter & Eliza Hall Institute of Medical Research 

Dr Rajith Aturaliya (PhD Student, 2003-2008) – Employed as Operations Manager, Pfizer Animal Genetics, Australia. Current position - Manager PricewaterhouseCoopers. 

Dr Markus Kerr (PhD Student, 2002-2006) – Employed as Humboldt Research Fellow, Max Planck Institute for Infection Biology, ARC DECRA Fellow, The University of Queensland. Currently enrolled in Master of Medical Imaging Science, University of Sydney. 

Dr Kevin Miranda (PhD Student, 2000-2004) - Employed by IBM Thomas J Watson Research Center, USA before moving to Dennis Brown Lab, Massachusetts General Hospital, Harvard University, Boston USA. Current position - Field Applications Scientist, Illumina.

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