Professor Jürgen Götz – Centre for Ageing Dementia Research (CADR)

Professor Jürgen Götz

 Contact Information

  j.goetz@uq.edu.au
  Building: QBI Building #79
  Room: 344
  Tel: +61 7 334 66329

 Mailing Address

  Queensland Brain Institute
  The University of Queensland
  Brisbane, 4072
  Queensland,
  Australia

Short biography

Jürgen Götz studied biochemistry at the University of Basel, and earned his PhD in immunology in the laboratory of Nobel Laureate Georges Köhler at the Max-Planck-Institute in Freiburg, Germany (1989). After postdoctoral work at UCSF and the Preclinical Research Division at Novartis Ltd in Basel, he established his reputation in the Alzheimer’s field as a research group leader at the University of Zürich (1994–2005). From 2005 - 2011, he has been Chair of Molecular Biology and Director of the Alzheimer’s and Parkinson’s Laboratory at the Brain and Mind Research Institute of the University of Sydney. In February 2012 he took up the position as Foundation Chair of Dementia Research at The University of Queensland and inaugural director of the Centre for Ageing Dementia Research (CADR) at the Queensland Brain Institute (QBI).

Research directions

It is hard to believe that, despite it being more than a century since the neuropathologist Alois Alzheimer identified the first published case of "presenile dementia", which his colleague Kraepelin would later identify as Alzheimer's disease, there is still no treatment that prevents the relentless neuronal degeneration that is characteristic of this condition. Among Alzheimer’s most important discoveries was the identification of two hallmark brain lesions, amyloid plaques and neurofibrillary tangles. The plaques are made of a small peptide called amyloid-beta, whereas the tangles are composed of the protein tau. Interestingly, as only discovered in the late 1990s, mutations in the genes that encode these proteins do cause inherited forms of dementia. By integrating these histopathological and genetic findings an important implication is that understanding how amyloid-beta and tau cause neurodegeneration is at the heart of finding a cure.
During the past 15 years, my research has focussed on understanding the role of tau and amyloid-beta, and their interaction, in the aetiology of Alzheimer’s disease. A key achievement in this regard was the establishment of the first mouse model with a tau pathology, an essential step in understanding the disease and working towards a cure. As soon as mutations were identified in the gene that encodes tau I expressed these in mice which resulted in more advanced mouse models, including those with authentic neurofibrillary tangle formation. I then correlated tau aggregation with memory impairment, which added to the validity of these models and subsequently helped in validating the efficacy of therapeutic interventions.
In work published in the journal Science I showed that amyloid-beta is upstream of tau. This seminal finding proved the amyloid cascade hypothesis, in essence revealing that reducing amyloid-beta should also abolish the toxic down-stream effects of tau. However, tau is not simply a bystander in this process. In work published in the top journal Cell we showed in 2010 that by modulating or removing tau, the toxicity of amyloid-beta is fully abrogated. In fact, by elucidating the underlying molecular mechanism we developed successful therapeutic strategies in mice.
My other major contributions to the field were discovering how tau pathology causes Parkinsonism, how the cellular power plants, the mitochondria, are impaired by tau and amyloid-beta, and what the relationship is between two pandemic diseases, type 2 diabetes and Alzheimer’s disease. I have also demonstrated on mouse models that sodium selenate, and a tau-based immunisation approach, are viable strategies for the latter condition.
We have established the roundworm C. elegans in the laboratory, an experimental system of less complexity that is used to complement studies in mice and cell lines. My current interest is in understanding the role of tau under both physiological and pathological conditions and in how amyloid-beta and tau interact.

Selected publications

 

1. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J (2010) Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models, Cell 142: 387–97

A paradigm shift linking the two hallmarks of Alzheimer’s disease, amyloid-β and tau, in the dendrite; full rescue of Alzheimer’s disease-associated phenotype was achieved in amyloid-β-forming mice, both genetically and pharmacologically.

2. Ittner LM, Fath T, Ke Y, Bi M, van Eersel J, Li KM, Gunning P and Götz J (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia, Proc Natl Acad Sci USA 105: 15997–16002

A model of Dopa-responsive early-onset Parkinsonism, identifying impaired axonal transport as a central patho-mechanism. Tau traps the kinesin adapter protein JIP1 in the soma, suggesting JIP1 as a drug target.

3. Götz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia, Nature Rev. Neurosci. 9: 532–44 [Featured article, July]

One of my major reviews of transgenic models of neurodegeneration, and the basis for my plenary lecture (more than 1,000 participants) at the prestigious ICAD08 (International Conference on Alzheimer’s Disease) meeting.

4. Chen F, Wollmer A, Hoerndli F, Münch G, Kuhla B, Rogaev EI, Tsolaki M, Papassotiropoulos A, Götz J (2004) Role for glyoxalase I in Alzheimer’s disease, Proc Natl Acad Sci USA 101: 7687–92

Demonstrating the potential of transcriptomics applied to models of neurodegeneration, and identifying a role for glyoxalase I in detoxifying methylglyoxal (a metabolite linked to mutagenesis, ageing and diabetes) in neurons.

5. Kins S, Crameri A, Evans DRH, Hemmings BA, Nitsch RM, Götz J (2001) Reduced PP2A activity induces abnormal phosphorylation and compartmentalization of tau in transgenic mice, J. Biol. Chem. 276: 38193–38200

Novel approach of dominant negative mutant expression of the protein phosphatase 2A’s (PP2A’s) catalytic subunit – the complete knockout is lethal –identified its neuronal substrates and the specific regulatory subunits involved.

6. Götz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Abeta42 fibrils, Science 293: 1491–95

Long-sought evidence for the amyloid cascade hypothesis that links amyloid-β and tau (the two hallmark lesions) in Alzheimer’s disease, highlighted by an accompanying ‘Perspectives’ article in Science.

7. Shmerling D, Hegyi I, Fischer M, Blättler T, Brandner T, Götz J, Rülicke T, Flechsig E, Cozzio A, Mering C, Hangartner C, et.al. (1998) Expression of amino-terminally trun¬cated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93: 203–14

Prions are infectious agents of transmissible diseases including mad cow disease. Using a combinatorial transgenic approach we identified functional domains of the Prion protein that are necessary for its infectivity.

8. Götz J, Probst A, Ehler E, Hemmings B, Kues W (1998) Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Cα. Proc Natl Acad Sci USA 95: 12370–75

The first gene targeting study of the heterotrimeric enzyme PP2A showing its essential role in forming the mesoderm, one of the three primary germ layers in the early embryo.

9. Götz J, Probst A, Spillantini MG, Schäfer T, Jakes R, Bürki K, Goedert M (1995) Somato-dendritic localisation and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14: 1304–13

The first tau transgenic mouse model; we revealed that the mice had a pre-tangle phenotype, a critical foundation for the development of human treatment strategies targeting tau.

10. Hebert JM, Rosenquist T, Götz J, Martin GR (1994) FGF5 as a regulator of the hair growth:
Evidence from targeted and spontaneous mutations. Cell 78: 1017–25

The basis for identifying and validating the growth factor Fibroblast Growth Factor 5 (Fgf5) as a crucial gene in hair length, with possible pharmaceutical implications for the treatment of alopecia.

 


 

 


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