Robert Richards

Professor Robert Richards

Head of Discipline of Genetics

School of Biological Sciences

Faculty of Sciences

Eligible to supervise Masters and PhD - email supervisor to discuss availability.


Research into a common mechanism for neurodegenerative diseases that have genetic hallmarks of autoinflammatory disease mechanism.
See https://doi.org/10.1093/hmg/ddy139

Dynamic Mutation Disorders: Mechanism of Pathogenesis in Neurodegenerative Repeat Expansion Diseases

The term “dynamic mutation” was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation (Richards, 2001b). The past two decades have seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases (including Huntington’s Disease) in addition to all of the characterised ‘rare’ chromosomal fragile sites. The common properties of the repeats in different diseases and fragile sites have given insight into this unique form of DNA instability. While the dynamic mutation mechanism explains some of the unusual genetic characteristics of the relevant diseases, unexpected findings have raised new questions and challenged some assumptions about the pathways that lead from mutation to disease (Richards and McLeod 2005). This project is aimed at understanding the molecular mechanisms involved in the pathogenic pathways that lead from expanded repeats to the diseases with which they are associated (McLeod et al., 2005; Lawlor et al., 2011; Samaraweera et al., 2013).

Is there a Common Pathogenic Pathway in the Dynamic Mutation Diseases? – Studies in Drosophila

Several human genetic diseases are thought to be caused by polyglutamine repeats that expand in copy number beyond a threshold (e.g. Huntington’s disease). There are, however, numerous other neurodegenerative diseases that have very similar clinical symptoms to the polyglutamine diseases and are due to expanded repeats, but these repeats cannot encode polyglutamine. We have therefore used transgenic Drosophila models of these repeat expansion diseases in order to test hypotheses in regard to whether there might be common pathogenic pathways for dynamic mutation diseases.

We have specifically assessed 1) whether RNA might be the pathogenic agent [as has been shown for CUG expansion in myotonic dystrophy] 2) whether polyalanine might be the common agent (by virtue of frameshift slippage) 3) whether apoptosis initiated by DNA breakage of the expanded repeat (as is seen for rare chromosomal fragile sites) might be the common pathogenic pathway.

In each case the transgenic Drosophila analysis has been able to rule out the hypothesis being tested. Therefore the likelihood is that polyglutamine is the pathogenic agent for those diseases with the capacity to translate their expansion into polyglutamine and that a distinct pathogenic mechanism exists for those related diseases where the repeat is unable to encode polyglutamine. These results favour the view that the intrinsic properties of the polyglutamine containing proteins are likely to contribute to the pathology. Further experiments will be undertaken to validate this view.

Neurodegenerative diseases have genetic hallmarks of autoinflammatory disease

The notion that one common pathogenic pathway could account for the various clinically distinguishable, typically late-onset neurodegenerative diseases might appear unlikely given the plethora of diverse primary causes of neurodegeneration. On the contrary, an autoinflammatory pathogenic mechanism allows diverse genetic and environmental factors to converge into a common chain of causality. Inflammation has long been known to correlate with neurodegeneration. Until recently this relationship was seen as one of consequence rather than cause—with inflammatory cells and events acting to ‘clean up the mess’ after neurological injury. This explanation is demonstrably inadequate and it is now clear that inflammation is at the very least, rate-limiting for neurodegeneration (and more likely, a principal underlying cause in most if not all neurode- generative diseases), protective in its initial acute phase, but pernicious in its latter chronic phase (Richards et al., 2018)

Inflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism for cell death. Indeed genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology.  However, while there is growing evidence that inflammation-mediated cell death may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double stranded RNA causes inflammation-mediated cell death when expressed in Drosophila. Repeat expansion mutation therefore confers ‘non-self’ recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.

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  • Current Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2019 Principal Supervisor Autoinflammatory anti-viral RNA response as the pathogenic mechanism for expanded repeat neurodegenerative diseases Master of Philosophy Master Full Time Miss Claire Alice Finn
    2018 Principal Supervisor The mode of action of Bt insecticidal toxins Doctor of Philosophy Doctorate Full Time Mr Biko Kahare Muita
    2018 Co-Supervisor Investigation of the Molecular Machinery that Controls Cell Division to Allow Rational Cancer Chemotherapy Doctor of Philosophy Doctorate Full Time Mr David Liam Newman
    2017 Co-Supervisor Purine metabolic enzymes as therapeutic targets in MPS111A Doctor of Philosophy Doctorate Full Time Miss Laura Jade Hewson
    2015 Principal Supervisor Molecular Mechanisms of Neurodegenerative Disease Doctor of Philosophy Doctorate Full Time Andrew William Scott
  • Past Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2013 - 2017 Principal Supervisor Investigating Biological Functions of the Tumor Suppressor WWOX in Drosophila Melanogaster Doctor of Philosophy Doctorate Full Time Mr Cheng Shoou Lee
    2011 - 2015 Principal Supervisor Defining the role(s) of non-classical tumour suppressor WWOX in cellular function using Drosophila melanogaster genetic modelling Doctor of Philosophy Doctorate Full Time Dr Amanda Choo
    2011 - 2015 Co-Supervisor ANALYSING THE ROLE OF AUTOPHAGY IN ALZHEIMER'S DISEASE PATHOGENESIS USING THE ZEBRAFISH MODEL SYSTEM Doctor of Philosophy Doctorate Full Time Mr Swamynathan Ganesan
    2010 - 2014 Principal Supervisor Targeting chromosomal instability: Screening and characterization of CIN killers Doctor of Philosophy Doctorate Full Time Mr Zeeshan Shaukat
    2009 - 2013 Principal Supervisor Double-Stranded RNA as a Pathogenic Agent in a Drosophila Model of Dominant Expanded Repeat Disease Doctor of Philosophy Doctorate Full Time Miss Saumya Samaraweera
    2007 - 2012 Principal Supervisor Investigation of Pathways Responsible for Repeat RNA-Mediated Cellular Perturbation in Drosophila Models of Dominant Expanded Repeat Disease Doctor of Philosophy Doctorate Full Time Mr Kynan Lawlor
    2006 - 2009 Co-Supervisor Fluorescent Imaging of Cell Division Doctor of Philosophy Doctorate Full Time Dr Saman Ebrahimi
    2006 - 2010 Principal Supervisor Investigation of RNA-Mediated Pathogenic Pathways in a Drosophila Model of Expanded Repeat Disease Doctor of Philosophy Doctorate Full Time Dr Clare van Eyk
    2004 - 2010 Principal Supervisor Huntingtin Function During Zebrafish (Danio rerio) Development Doctor of Philosophy Doctorate Full Time Miss Tanya Henshall
    2003 - 2008 Co-Supervisor Zebrafish as a Model of Genetic Disease Doctor of Philosophy Doctorate Full Time Dr Ben Tucker
    2003 - 2008 Principal Supervisor The Genetic and Biochemical Analysis of Drosophila Wwox Protein Function Doctor of Philosophy Doctorate Full Time Mr Alexander Colella
    2002 - 2007 Principal Supervisor Investigating the Role of Huntingtin in Development and Disease using the Zebrafish Model Organism Doctor of Philosophy Doctorate Full Time Ms Amanda Lumsden
    2002 - 2006 Principal Supervisor Investigation of the Pathogenic Agent in a Drosophila Model of Polyglutamine Disease Doctor of Philosophy Doctorate Full Time Miss Catherine McLeod
  • Position: Head of Discipline of Genetics
  • Phone: 83137541
  • Email: robert.richards@adelaide.edu.au
  • Fax: 8313 7534
  • Campus: North Terrace
  • Building: Molecular Life Sciences, floor 1
  • Room: 1 35
  • Org Unit: Molecular and Biomedical Science

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