Prof Grant Dewson, Lab Head | WEHI Researcher Profile

Q: Blocking cell death in Parkinson's disease

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. 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.

Q: Ubiquitin signalling in neuroblastoma

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.

Q: Understanding Parkinson's disease heterogeneity

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.

Q: Developing better models of Parkinson's disease

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.

Q: Characterising mitochondrial quality control

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.

Q: Ubiquitin signalling as an arbiter of cell fate

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.Resources: https://www.wehi.edu.au/news/fine-tuning-cell-death-new-component-death-machinery-revealed

About

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.

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Publications

Selected publications from Prof Grant Dewson

Lang T, McLean I, Shin J, Jackson V, Lawrenson I, Zipper B, Yeung A, Evans A, Dewson G. The diagnostic pathway of Parkinson’s disease: understanding patient perspectives in Australia. npj Parkinson’s Disease. 2025;11(1):10.1038/s41531-025-00968-3

Li K, Yap YQ, Moujalled DM, Sumardy F, Khakham Y, Georgiou A, Jahja M, Lew TE, De Silva M, Luo M-X, Gong J-N, Yuan Z, Birkinshaw RW, Czabotar PE, Lowes K, Huang DCS, Kile BT, Wei AH, Dewson G, van Delft MF, Lessene G. Differential regulation of BAX and BAK apoptotic activity revealed by small molecules. Science Advances. 2025;11(10):10.1126/sciadv.adr8146

Glover HL, Schreiner A, Dewson G, Tait SWG. Mitochondria and cell death. Nature Cell Biology. 2024;26(9):10.1038/s41556-024-01429-4

Yuan Z, van Delft MF, Li MX, Sumardy F, Smith BJ, Huang DCS, Lessene G, Khakam Y, Jin R, He S, Smith NA, Birkinshaw RW, Czabotar PE, Dewson G. Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis. PLOS Biology. 2024;22(5):10.1371/journal.pbio.3002617

Gan ZY, Callegari S, Nguyen TN, Kirk NS, Leis A, Lazarou M, Dewson G, Komander D. Interaction of PINK1 with nucleotides and kinetin. Science Advances. 2024;10(3):10.1126/sciadv.adj7408

Frank D, Bergamasco M, Mlodzianoski MJ, Kueh A, Tsui E, Hall C, Kastrappis G, Voss AK, McLean C, Faux M, Rogers KL, Tran B, Vincan E, Komander D, Dewson G, Tran H. Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth. eLife. 2023;12:10.7554/elife.90796.3

Frank D, Bergamasco M, Mlodzianoski MJ, Kueh A, Tsui E, Hall C, Kastrappis G, Voss AK, McLean C, Faux M, Rogers KL, Tran B, Vincan E, Komander D, Dewson G, Tran H. Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth. eLife. 2023;12:10.7554/elife.90796

Dewson G, Eichhorn PJA, Komander D. Deubiquitinases in cancer. Nature Reviews Cancer. 2023;23(12):10.1038/s41568-023-00633-y

Birkinshaw RW, Iyer S, Lio D, Luo C, Brouwer J, Miller MS, Robin A, Uren RT, Dewson G, Kluck RM, Colman PM, Czabotar PE. The crystal structure of detergent-activated BAK dimers provides insights into BAK activation steps and how they stabilise membrane pores. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s205327332308912x

Huang AS, Chin HS, Reljic B, Djajawi TM, Tan IKL, Gong J-N, 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. 2023;30(3):10.1038/s41418-022-01067-z

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Lab research projects

Blocking cell death in Parkinson’s disease

Ubiquitin signalling in neuroblastoma

Understanding Parkinson’s disease heterogeneity

Developing better models of Parkinson’s disease

Characterising mitochondrial quality control

Ubiquitin signalling as an arbiter of cell fate

Student research projects

Characterising a novel mitochondrial damage control pathway and its importance in neurodegenerative disease

Honours/PhD

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Characterising a novel mitochondrial damage control pathway and its importance in neurodegenerative disease

Honours/PhD

More information

View all student research projects

Prof Grant Dewson

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