My team focuses on understanding the molecular and co-ordinated control of the two fundamental pathways of apoptosis and mitophagy (mitochondrial quality control) and its importance to Parkinson’s disease and cancer.
Our research has led the field in understanding of how the fundamental cell process of apoptosis is controlled, how the apoptosis effector proteins BAX and BAK function to kill cells and has identified new avenues to manipulate their activity therapeutically.
More recently, my lab has highlighted a new level of integration between the machineries that control cell death and damage-induced mitophagy that might explain why defective activity of the key protein Parkin drives the pathology of early onset Parkinson’s disease. My lab has established and shared new animal and cell models to investigate Parkinson’s disease, mitochondrial biology, and cell death research.
We have established key collaborations with the clinic. With Dr Andrew Evans (Director, Movement Disorders Program, Royal Melbourne Hospital), we have a pipeline for the recruitment of Parkinson’s disease patients and the generation of patient-derived cells (dopaminergic neurons and astrocytes) to understand the disease in individuals and to accelerate clinical translation of our research.
United Kingdom, University of Leicester, PhD, 2002
United Kingdom, University of Nottingham, BSc (Hons), 1995
2019 Centenary Fellowship, Bodhi Education Fund
2011 Future Fellowship, Australian Research Council
2011 QEII Postdoctoral Fellowship, Australian Research Council
2006 Australian Research Council Postdoctoral Award
2020-2024 Ideas Grant, National Health and Medical Research Council
2020-2023 Project Grant, Worldwide Cancer Research
2017-2019 Harry Secomb Trust Award
2015-2017 Project Grant, National Health and Medical Research Council
2014-2016 Project Grant, National Health and Medical Research Council
2014-2017 Project Grant, Worldwide Cancer Research
2012 Project Grant, ANZ Hugh Williamson Foundation
Head, Parkinson’s Disease Research Centre
Head, International Student Program in Research Experience (InSPIRE)
Head, WEHI Strategic Alliances-Asia
Editorial Board, NPJ Parkinson’s Disease
Editorial Board, Cell Death and Disease
Editorial Board, Scientific Reports
Editorial Board, PLOS One
Huang AS, Chin HS, Reljic B, Djajawi TM, Tan IKL, Gong JN, Stroud DA, Huang DCS, van Delft MF, DEWSON G. Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins. CELL DEATH & DIFFERENTIATION. 2022. https://doi.org/10.1038/s41418-022-01067-z. PMID: 36171332
Schmidt MF, Gan ZY, Komander D, DEWSON G. Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities. CELL DEATH & DIFFERENTIATION. 2013. 152(3):519-31.PMID: 33414510
Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, DEWSON G, Glukhova A, Komander, D. Activation mechanism of PINK1. NATURE. 2021. 602:328-335. PMID: 34933320
Masaldan S, Callegari S, Dewson G. Therapeutic targeting of mitophagy in Parkinson’s disease. Biochem Soc Trans. 2022 Apr 29;50(2):783-797. doi: 10.1042/BST20211107.PMID: 35311891
Bernardini JP, Lazarou M, Dewson G. Parkin and mitophagy in cancer. Oncogene. 2017 Mar;36(10):1315-1327. PMID: 27593930.
Li K, van Delft MF, Dewson G. Too much death can kill you: inhibiting intrinsic apoptosis to treat disease. EMBO J. 2021 Jul 15;40(14):e107341. doi: 10.15252/embj.2020107341. PMID: 34037273
Sandow JJ, Tan IK, Huang AS, Masaldan S, Bernardini JP, Wardak AZ, Birkinshaw RW, Ninnis RL, Liu Z, Dalseno D, Lio D, Infusini G, Czabotar PE, Webb AI, DEWSON G. Dynamic reconfiguration of pro-apoptotic BAK on membranes. EMBO J. 2021. 40(20):e107237.
Chin HS, Li MX, Tan IKL, Scicluna K, Kelly GL, Chappaz S, Khaw SL, Chang C, Sandow JJ, Hockings C, Hall CM, Kueh AJ, Reljic B, Ryan MT, Kluck RM, P Bouillet1,2, Herold MJ, Gray DHD, Huang DCS, van Delft MF DEWSON G.
VDAC2 enables BAX to mediate apoptosis and limit tumour development. NATURE COMMUNICATIONS. 2018. 9(1):4967.
McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, Geoghegan ND, Chappaz S, Davidson S, San Chin H, Lane RM, Dramicanin M, Saunders TL, Sugiana C, Lessene R, Osellame LD, Chew TL, DEWSON G, Lazarou M, Ramm G, Lessene G, Ryan MT, Rogers KL, van Delft MF, Kile BT. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. SCIENCE. 2018. 359(6378). PMID: 29472455
Li MX, Tan IKL, Ma SB, Hockings C, Kratina T, Dengler MA, Alsop AE, Kluck RM, Dewson G. BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove. Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7629-7634. PMID: 28673969.
Schenk RL, Strasser A, Dewson G. BCL-2: Long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun. 2017 Jan 15;482(3):459-469. PMID: 28212732.
Uren RT, O’Hely M, Iyer S, Bartolo R, Shi MX, Brouwer JM, Alsop AE, Dewson G, Kluck RM. Disordered clusters of Bak dimers rupture mitochondria during apoptosis. Elife. 2017 Feb 6;6. pii: e19944. PMID: 28182867.
Ma SB, Nguyen TN, Tan I, Ninnis R, Iyer S, Stroud DA, Menard M, Kluck RM, Ryan MT, Dewson G. Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: A requirement for VDAC2 or Bak for efficient Bax apoptotic function. Cell Death Differ. 2014. Dec;21(12):1925-35. PMID: 25146925
Ma S, Hockings C, Anwari K, Kratina T, Fennell S, Lazarou M, Ryan MT, Kluck RM, Dewson G. Assembly of the Bak apoptotic pore: a critical role for the Bak protein alpha6 helix in the multimerization of homodimers during apoptosis. The J Biol Chem. 2013 Sep 6;288(36):26027-38. PMID: 23893415.
Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell. 2013 Jan 31;152(3):519-31. PMID: 23374347.
Dewson G, Ma S, Frederick P, Hockings C, Tan I, Kratina T, Kluck RM. Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ. 2012 Apr;19(4):661-70. PMID: 22015607.
Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol Cell. 2009 Nov 25;36(4):696-703. PMID: 19941828.
Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol Cell. 2008 May 9;30(3):369-80. PMID: 18471982.
Parkinson’s disease movement symptoms are caused by the progressive death of dopamine-producing neurons. However, how and why these particular neurons die in Parkinson’s is unclear. Our research aims to answer these questions to enable targeted cell death inhibition as an avenue for drugs that can stop or slow neurodegeneration.
People: Marlene Schmidt (PhD), Alex Yeung (PhD), Kaiming Li (PhD).
Collaborators: Guillaume Lessene, Mark van Delft.
My lab utilises novel cell biology and biochemical approaches to interrogate how apoptosis is controlled so that we might better target the process to treat disease. We have identified several novel putative regulators of apoptosis. This project will characterise the role of these proteins in regulating cell death and also investigate their potential role in cancer development.
The project will involve diverse approaches including cell culture, mutagenesis, protein chemistry, mass spectrometry and high-resolution microscopy.
Neuroblastoma is the most common childhood cancer. Whilst in some children the cancer spontaneously resolves, other children have very poor prognosis and respond poorly to aggressive chemotherapy. Our research aims to characterise the putative tumour suppressor function of the E3 ubiquitin ligase Parkin in poor prognosis neuroblastoma. We also aim to identify new therapeutic targets to treat neuroblastoma through genetic screening.
Supported by Worldwide Cancer Research.
People: Ziyan Liu (PhD), Shuai Huang (Postdoc), Iris Tan (Postdoc)
Parkinson’s disease is a highly complex neurodegenerative condition. We need to understand this complexity to take a precision-medicine approach to treat the disease. In collaboration with leading Movement Disorders clinicians at The Royal Melbourne Hospital, we are using cutting-edge and complementary approaches to characterise cells derived from people with Parkinson’s (dopaminergic neurons, astrocytes) to determine their vulnerabilities.
People: Alex Yeung (PhD), Marlene Schmidt (PhD), Shashank Masaldan (Postdoc), Iris Tan (Postdoc), Tahnee Saunders (Postdoc), Dr Andrew Evans (RMH)
Current Parkinson’s models do not fully reflect the chronic and heterogeneous nature of the disease. We are using cutting edge approaches to develop models that replicate the genetic defects in people with Parkinson’s to provide better tools for drug discovery.
People: Shashank Masaldan (Postdoc), Marlene Schmidt (PhD), Tahnee Sauners (Postdoc)
Defective mitochondrial quality control is known to drive inflammation, cell death and is linked to Parkinson’s disease. In collaboraton with the Lazarou lab (Ubiquitin Signalling division, WEHI), we are investigating the mechanisms by which cells (including Parkinson’s patient cells) respond to mitochondrial damage and stress.
People: Tahnee Saunders (Postdoc)
We are exploring the role of ubiquitin enzymes (ligases and deubiquitinases) in the control of cell survival, function and inflammation. These enzymes may represent novel therapeutic targets to either limit cell death in degenerative disease or promote cell death in cancer treatment.
People: Hoanh Tran (Postdoc) Shuai Huang (Postdoc)