Hatters Group

“We investigate novel methods and approaches to study the aggregation behaviour of proteins which are the hallmark of neurodegenerative diseases such as Huntington’s, Alzheimer’s and Motor Neuron Disease (MND). The hope is that we can identify some therapeutic targets” – Danny Hatters

Research

Detecting and mapping different protein conformations in live cells

Many cellular functions are driven by changes in the conformation of proteins; some conformational changes act as molecular switches for regulating normal cellular activities, while others are non-normal and result in detrimental outcomes to the cell. Our laboratory studies how proteins change conformation in live cells and how different conformations engage with the surrounding cellular machinery.

A key platform is the development of new fluorescence-based approaches for visualization of distinct conformations of specific disease associated proteins, such as those involved in cancer and neurodegenerative disease.

Tracking the aggregation kinetics of mutant proteins in cells

A major area of research is defining how abnormal conformations of mutant proteins aggregate and interfere with the cellular machinery. One such protein we study is huntingtin, which when mutated causes Huntington’s disease.

Huntington’s disease is a devastating neurodegenerative disease often striking individuals mid-life. The disease is caused by an abnormally long polyglutamine repeat length near the amino-terminus of huntingtin. The extra glutamines cause the protein to change conformation, aggregate and form large aggregates known as inclusions.

We also study the aggregation process of other proteins that also lead to disease, such as superoxide dismutase 1 in Motor Neuron Disease and a family of proteins that have polyalanine expansions in a manner analogous to the polyglutamine expansions.

In vivo Drosophila models of Huntington’s disease

For a more comprehensive view on how protein structure, conformation and aggregation play roles in intact living systems we are developing novel Drosophila

models of Huntington’s disease in collaboration with Dr Leonie Quinn, in the Department of Anatomy and Neuroscience. We are devising novel imaging approaches, which includes live-cell imaging, to specifically examine protein dynamics in vivo.

Visualizing “on” and “off” kinase conformations in cells

In collaboration with Dr Terry Mulhern and Dr David Huang of the Walter and Eliza Hall Institute we are using novel structure-guided approaches to develop sensors that can map where different kinase conformations accumulate in live cells. We anticipate that this will enable a better understanding of how “on” and “off” forms of kinases specifically interact with different cellular proteins and ligands, and how the different forms are trafficked around the cell.

Techniques

Typically these include classic biophysics and structural biology approaches for examining protein structure and function, and genetics and classic cell biology approaches for examining how proteins work in their natural environment.

We have also developed new biosensors and flow cytometry procedures to track the different conformations of proteins in cells, including:

  • use of the department's new flow cytometry instrument, the BD LSRFortessa
  • the fluorescence detection module on the analytical ultracentrifuge
  • They also use the new high-end fluorescence microscopes for high resolution and live cell imaging.

Group Members

Biography

Danny Hatters runs a program exploring how proteins change conformation in cells as part of normal and pathogenic processes, including those associated with misfolding and aggregation.  Key elements of this research include the development and application of new fluorescence -based probes and biosensors to view protein dynamics in cells.  His major area of research is in Huntington's Disease with other programs in motor neuron disease and cancer. He completed his PhD at the University of Melbourne in 2002.  He then did a post doc at the Gladstone Institutes/University of California, San Francisco under the mentorship of Dr Karl Weisgraber for 5 years until 2007. There he studied how three variants of apolipoprotein E, apoE2, apoE3 and apoE4 differ in their conformation and biophysical properties as a basis for understanding the mechanisms underlying the elevated risk that the apoE4 isoform confers for Alzheimer's disease. In April 2007, he returned to Melbourne to take up a CR Roper Fellowship position in the Department of Biochemistry and Molecular Biology. In 2009 he was awarded the Grimwade Fellowship to continue developing his own research program focusing on how protein conformations lead to cellular dysfunction and disease.  In 2012, he was awarded an ARC Future Fellowship.