Discovery of polyQ ataxin-1 regulation and regulators
The worldwide impact of the broad spectrum of neurodegenerative diseases is staggering: >35 million people experience debilitating dementia and cognitive decline, most commonly in the progression of Alzheimer’s disease, but millions more suffer the loss of coordinated movement and memory in neurodegenerative conditions such as Parkinson’s disease, Huntington’s disease, and the Spinocerebellar Ataxias (SCAs). Polyglutamine (PolyQ) expansions in ataxin-1, an RNA-binding protein with poorly understood physiological and pathophysiological roles, are the cause of neurodegeneration in Spinocerebellar Ataxia 1 (SCA1). A robust feature of polyQ-ataxin-1 is its formation of prominent nuclear bodies comprised of polyQ-expanded ataxin-1 together with other, mostly uncharacterized, partners, but how ataxin-1 influences cellular functions has remained poorly understood. We recently discovered that several nuclear transport proteins are proximal partners of polyQ-ataxin-1, and that expression of polyQ ataxin-1 is sufficient to disturb the cytosolic milieu and negatively impact cell survival. Furthermore, we observed a stress-induced remodelling of ataxin-1 intranuclear bodies typical of a transition to a hydrogel-state, a hallmark of neurotoxicity. Our studies open exciting new avenues to probe the mechanisms of ataxin-1-induced toxicity by defining the impact of ataxin-1 on nucleocytoplasmic transport and characterizing stress-dependent remodelling of ataxin-1 nuclear bodies. Key methodologies used in these projects will include high resolution and live imaging, as well as proteomics approaches to define the ataxin-1 interactome.
Asocciate Professor Danny Hatters, Bio21
Dr Liz Hinde, UNSW
Professor David Jans, Monash University
Professor Annalisa Pastore, UK
This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
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- Chen WK, Yeap YY, Bogoyevitch MA. The JNK1/JNK3 interactome - Contributions by the JNK3 unique N-terminus and JNK common docking site residues. Biochem Biophys Res Commun 2014;453(3): 576-81.
- Hinde E, Pandzic E, Yang Z, Ng IHW, Jans DA, Bogoyevitch MA, Gratton E, Gaus K. Quantifying the dynamics of the oligomeric transcription factor STAT3 by pair correlation of molecular brightness. Nature Communications 2016; 7:11047.
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