Open positions

Projects are available in Alzheimer’s and Parkinson’s Disease research

recruiting at the level of Honours and PhD students as well as Postdocs

The Alzheimer’s and Parkinson’s Disease (A+PD) Laboratory aims to attract the brightest students and postdocs. For PhD students who have secured APA scholarships we will provide a top-up of AU$5,000 p.a. Overseas students are encouraged to apply, provided they have secured full scholarships, including tuition fees.

Laboratory: The Alzheimer’s and Parkinson’s Disease Laboratory is based at the Brain & Mind Research Institute (BMRI) of The University of Sydney in Mallett St, close to the University’s Camperdown Campus. The laboratory is well equipped to perform molecular and cellular work (ELISA reader, LifeCycler, Versadoc, etc). It has its own histology unit, a micromanipulation set-up to generate transgenic mice, a ballistic set-up to generate transgenic C. elegans strains, and a tissue culture laboratory with several incubators and laminar flows. The laboratory has access to state-of-the-art behavioural facilities.

Research in the A+PD Laboratory: The laboratory is internationally recognised for its cutting edge research in Alzheimer’s disease and related neurodegenerative disorders. The laboratory focuses on the development of animal (mouse and C. elegans) and cellular models to unravel the causes of Alzheimer’s disease. It uses molecular and functional genomics techniques (proteomics, transcriptomics, miRNA analysis) to dissect the underlying pathomechanisms, and it uses a wide range of approaches to find a treatment for these debilitating diseases. It has a major interest in the microtubule-associated protein Tau and its interacting proteins, in the tau kinase PP2A (protein phosphatase 2A), and in amyloid-beta (Abeta).

Available projects:

(1) Mapping of protein/protein interactions as a treatment approach – Using our own transgenic Alzheimer mouse models followed by a functional validation in human Alzheimer’s disease tissue we have identified pathological protein/protein interactions (such as Tau/Jip1 or Tau/Fyn or NMDAR/PSD95) that have a causal role in disease. The project(s) will involve the mapping and narrowing down of these interactions and using this information to screen inhibitors of these interactions.

(2) The role of geriatric conditions in AD pathology  – a combinatorial approach – We have crossed tau mutant mice (a model of the tau pathology in Alzheimer’s disease) with SAMP8 mice (a strain with accelerated senescence) to determine whether a geriatric condition can accelerate the pathology in mice that are pre-disposed to develop a tau pathology.  By determining SNPs that are associated with the SAMP8 phenotype we aim to identify modifiers of the tau pathology, to get insight into AD pathogenesis and to use this information for a therapy.

(3) Modifier screen of Parkinsonism – We have established a mouse strain, K3, that is characterised by a very early onset of memory impairment, Parkinsonism and amyotrophy. Crossing this strain with ENU-mutagenised mice established pedigrees with an augmented and ameliorated phenotype, respectively. The project will involve the characterisation of these new mouse strains and an analysis of the ENU-mutated genes and their roles under both physiological and pathological conditions.

(4) C. elegans models of neurodegeneration – Based on our findings in mouse models of Alzheimer’s disease (AD) and related dementing disorders such as Frontotemporal dementia (FTD) we have established worm strains with both a conditional and constitutive expression of mutant forms of genes that are implicated in humans forms of disease. The project will involve the characterisation of these strains histologically, biochemically and behaviourally.

(5) Selective vulnerability – The K369I tau-expressing K3 mouse strain is characterized by a progressive loss of TH (tyrosine hydroxylase)-positive neurons in the substantia nigra. By two years of age, 60% of the TH-positive neurons are gone. What protects some neurons while others degenerate others is not understood. The project will involve Affymetrix screening in mice followed by a rescue in C. elegans followed by a therapy in the K3 mice using viral (AAV) methods.

(6) Mechanisms of tau-mediated Aβ toxicity Tau is essential for Abeta to mediate its toxic effects including excitotoxic signaling. This project will assess the structural changes in the spine that make mice in which the interaction of NMDAR and PSD95 has been transiently disrupted permanently resistant to Abeta toxicity.

(7) Target validation of deregulated miRNAs, mRNAs and proteins in Alzheimer’s disease – As part of our Functional Genomics efforts, we are constantly identifying deregulated miRNAs, mRNAs and proteins in our cellular and transgenic mouse models. The project will involve dissecting the roles of selected candidates in vivo followed by a functional validation in human tissue.

(8) Physiological function of tau isoforms – The laboratory has an increasing interest in understanding the function of the three murine and six human tau isoforms. This is not a pure academic exercise as in human disease (FTDP-17) a change in isoform ratios causes neurodegeneration and dementia. The project will involve developing tools such as monoclonal antibodies and using confocal microscopy and mass spectrometry to determine the specific role of the tau isoforms. A further project is in understanding site-specific phosphorylation under physiological conditions (20% of tau’s amino acids can be potentially phosphorylated.

(9) Commonalities of Alzheimer’s and type 2 diabetes – The laboratory has a long-standing interest in the commonalities of type 2 diabetes (with amyloidogenic amylin aggregating in islets) and Alzheimer’s (with amyloidogenic Abeta aggregating in brain). We have been applying iTRAQ quantitative proteomics followed by a functional validation of mitochondrial functions. Several projects are available in this area.

Recent publications:

Louis JV et al (2011) Mice lacking phosphatase PP2A subunit PR61/B’δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β, PNAS 108:6957-62  • Ittner LM & Götz J (2011) Amyloid-β and tau–a toxic pas de deux in Alzheimer’s disease, Nat Rev Neurosci 12: 65-72 • Ittner et al (2010) (2010) Dendritic Function of Tau Mediates Amyloid- β Toxicity in Alzheimer’s Disease Mouse Models, Cell 142: 387-397 [Highlighted in Nat Rev Neurosci Sep 2010] • van Eersel et al (2010) Sodium selenate treatment mitigates tau pathology in Alzheimer’s disease models, PNAS 107: 13888-93 • Rhein V et al (2009) Aβ and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice, PNAS 106: 20057 [Highlighted in Nat Rev Neurosci Jan 2010] • Ittner LM et al (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia, PNAS 105: 15997 • Götz J & Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia, Nat Rev Neurosci 9: 532  • Habicht G et al (2007) Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils, PNAS, 104: 19232

For more details please contact Prof. Jürgen Götz (j.goetz@uq.edu.au)