Dr Carol Dobson-Stone

Dr Carol Dobson-Stone, Senior Research Fellow, The University of Sydney.

Carol completed her PhD in human genetics at the University of Oxford, UK, in 2004. Shortly thereafter, she was awarded an EMBO Fellowship to work on brain function genetics at the Garvan Institute of Medical Research, moving to Neuroscience Research Australia in 2006. She was appointed as a Senior Research Fellow to the Brain and Mind Centre at the University of Sydney in 2017. Dr Dobson-Stone is a molecular geneticist and has led several NHMRC Project Grants examining genes that are mutated in dementia and related neurodegeneration, particularly frontotemporal dementia and motor neuron disease/amyotrophic lateral sclerosis. She uses next-generation sequencing data from dementia patients to identify potentially pathogenic DNA variants in candidate genes. She is developing high-throughput cellular assays of dementia-relevant biological phenotypes, in order to determine pathogenicity of DNA variants. Carol's work also involves in-depth characterisation of candidate disease genes using molecular biological and cell culture assays. Her research team investigates genes that are mutated in dementia and related neurodegeneration, particularly frontotemporal dementia (FTD) and motor neuron disease (MND). Her research straddles multiple steps on the pathway from genetic disease to targeted therapy. They use whole-exome and whole-genome DNA sequencing data from dementia patients to identify potentially pathogenic DNA variants in candidate genes. They are also developing high-throughput cellular assays of dementia-relevant biological phenotypes, such as subcellular localisation and aggregation of key pathological proteins. These are used to determine pathogenicity of DNA variants in known dementia genes, and prioritise variants in novel candidate genes for further analysis. They also perform in-depth characterisation of candidate disease genes using molecular biological and cell culture assays.

Forefront Group:

  • BMC Neurogenetics and Epigenetics Research Group
  • BMC Dementia Neurogenomics Research Group

Affiliate Organisations

Senior Research Fellow, Central Clinical School, University of Sydney
Conjoint Senior Lecturer, School of Medical Sciences, UNSW NHMRC Boosting Dementia Research Leadership Fellow

Neurodegeneration of interest:



  • Genetics
  • Molecular biology
  • Cell culture

Specific Skills:

  • Molecular Biologist
  • Microplate reader assays
  • DNA sequencing
  • Genotyping
  • Repeat expansion PCRs
  • Cellular assays


CIA on NHMRC Project Grant 1140708, 'The role of mutant CYLD in frontotemporal dementia and motor neuron disease'

CIC on NHMRC Project Grant 1163249, 'Mutations in genes causal of white matter disease and dysregulation of lipid metabolism in frontotemporal dementias'

[Sole CI on NHMRC Boosting Dementia Research Leadership Fellowship 1138223, ‘Discovery of novel neurodegeneration genes via next-generation sequencing technologies and high-throughput cellular assays’]

Project - The role of mutant CYLD in frontotemporal dementia and motor neuron disease

List all Chief investigators and associate investigators

CIA, Carol Dobson-Stone; CIB, John Kwok; CIC, Ian Blair; CID, Julie Atkin; CIE, Lezanne Ooi; CIF, Arne Ittner; CIG, Albert Lee; CIH, Karen Mather AI, Elizabeth Thompson; AI, Gaetan Burgio

Research Project Abstract

Our understanding of FTD and MND has been greatly enhanced by the identification of the genes and pathways that underlie these disorders. Positional cloning of a large, multi-generational family with FTD and MND has identified a new disease gene, CYLD. CYLD encodes an enzyme involved in autophagy and mutations can cause benign skin tumours. In contrast to all previous CYLD mutations, the M719V mutation identified in the FTD-MND family significantly increases CYLD enzyme activity. The aims of this project are: to assess the impact of mutant CYLD on (i) CYLD-related proteins and (ii) the autophagy pathway, using transfected neuronal cell lines and induced pluripotent stem cells; (iii) to establish a M719V CYLD mutant mouse model and examine its behavioural and neuropathological phenotype; and (iv) to determine the contribution of rare and common variation in CYLD to differences in cognitive performance and disease risk in elderly cohorts. There are no effective cures for FTD or MND. Understanding the biological pathways that lead from CYLD mutation to brain cell death and identifying DNA variants that increase disease risk or specific cognitive deficits will help uncover the underlying pathogenic mechanism and generate cellular & animal models important for development of therapeutic agents. This project is funded from Jan 2018 – Dec 2021.

Challenges within the field

There is currently no FDA-approved medication for FTD and the only licensed MND treatment, riluzole, extends life by only 3 months on average. Thus, there is a pressing social and economic need for the identification of new targets and new drugs to treat these disorders. Identification of the biological consequences of the CYLD mutation could therefore provide targets for the development of new treatments and preventative therapies for this debilitating group of disorders. Being a tumour suppressor gene, it is clear that simple downregulation of CYLD activity will have adverse consequences. Therefore, identification of CYLD substrates/binding partners that are specifically affected by the M719V mutation is needed to identify therapeutic targets that may not impinge upon the tumour suppressor pathway.

Research Project Description

Aim 1: Identify changes in CYLD neurodegeneration-related proteins. CYLD is involved in diverse cellular functions, such as cell proliferation, apoptosis, Ca2+ signalling and inflammation. It is therefore possible that CYLDM719V exerts its pathogenic effect via multiple mechanisms. We will therefore take an unbiased approach to identify proteins that are (i) up- or down-regulated by CYLDM719V, (ii) CYLD binding partners, or (iii) substrates of CYLD deubiquitinase activity. All three classes of proteins could give clues to the nature of the pathway(s) involved in mutant CYLD pathogenesis and represent important therapeutic targets for FTD/MND.

Aim 2: Assess the impact of mutant CYLD on the autophagy pathway. Several FTD/MND genes have been implicated in autophagy. CYLD acts mainly on K63-linked ubiquitin chains, the major mode by which proteins are targeted for autophagy. It follows then that CYLDM719V may exert its pathogenic effect through disruption of autophagy. With growing evidence that autophagy impairment underlies FTD and MND, it is important to test mutant CYLD’s role in this process. We will determine how autophagosome production and autophagy substrate processing is affected, and examine the potential restorative effects of CYLD downregulation.

Aim 3: Establish an FTD-MND mutant CYLD mouse model. There is a paucity of mouse models for FTD-MND, which are needed for testing new drug therapies and for examining disease mechanisms in vivo. We will use CRISPR/Cas9 genome editing to establish a transgenic mouse model that expresses a Cyld M718V mutation mimicking the human M719V mutation. We will perform assays of memory, social cognition and motor function and neuropathological analyses to determine if the mouse recapitulates features of FTD or MND, and is therefore a valuable animal model of these diseases.

Aim 4: Determine the contribution of genetic variants affecting CYLD expression to dementia- related traits. Some genes can harbour both rare causal mutations that lead to Mendelian diseases, and more common single nucleotide polymorphisms (SNPs) that increase susceptibility to more complex traits. Since CYLDM719V, which leads to a marked increase in CYLD activity, is causative of FTD-MND, it is reasonable to hypothesise that common SNPs that affect CYLD expression levels may also affect cognition and/or risk of developing sporadic FTD/MND. We will perform a comprehensive survey of SNPs in the CYLD region to determine whether these common SNPs or rare variants affect risk of developing dementia or related traits in the general population, and identify how they affect CYLD expression.

Research Objectives

Aim 1: We expect to establish a cutting-edge cellular model of FTD-MND and use them to identify neuronal proteins that are affected by expression of the M719V mutation, perhaps highlighting molecular pathways hitherto unrecognised as being affected in FTD/MND.

Aim 2: We expect to identify how mutant CYLD impacts the autophagy pathway in neuronal cells, and whether its effects are mediated by NF-kB, and determine whether modulation of CYLD can alter autophagy pathways and ameliorate aberrant neuronal phenotypes, thus gaining insights into possible therapeutic strategies for FTD-MND.

Aim 3: We expect to generate a mouse model of the FTD-MND CYLD mutation. Should this mouse develop a behavioural and/or neuropathological phenotype, this would provide the FTD-MND research community with an animal model to help understand the biological pathways that lead to neurodegeneration and to test potential therapies.

Aim 4: We expect to identify common variants that alter CYLD expression, affect dementia-related traits and potentially also increase risk of developing sporadic disease.

Key Publications from this project

Dobson-Stone C*, Hallupp M, Shahheydari H, Ragagnin AMG, Chatterton Z, Carew-Jones F, Shepherd CE, Stefen H, Paric P, Fath T, Thompson EM, Blumbergs P, Short CL, Field CD, Panegyres PK, Hecker J, Nicholson G, Shaw AD, Fullerton JM, Luty AA, Schofield PR, Brooks WS, Rajan N, Bennett MF, Bahlo M, Shankaracharya, Landers JE, Piguet O, Hodges JR, Halliday GM, Topp SD, Smith BN, Shaw CE, McCann E, Fifita JA, Williams KL, Atkin JD, Blair IP, Kwok JB*. CYLD is a causative gene for frontotemporal dementia – amyotrophic lateral sclerosis. Brain (2020) 143:783-799 *joint senior authors

Infographic / Medical Diagram / Scientific Diagram / Picture


Key Findings

  • The CYLD M719V mutation leads to a significant upregulation of enzyme activity, more potent inhibition of the cell signaling molecule NF-B, and impairment of a key process in autophagy.
  • Primary neurons overexpressing the mutation show increased cytoplasmic localisation of TDP-43 and altered axonal morphology
  • Brain tissue from patients with mutant CYLD shows widespread glial CYLD immunoreactivity.
  • CYLD has not before been implicated in neurological disorders, and it therefore represents a potential new therapeutic target for FTD and ALS.
  • It also reinforces the importance of autophagy regulation in the pathogenesis of these disorders.