Universität Zürich

previous IMB
work groups

Homepage of the Institute


Jürgen Götz

In vivo models of Alzheimer's Disease

Jürgen Götz

present address:

Jürgen Götz
Professor (Chair of Molecular Biology)
Brain and Mind Research Institute
University of Sydney
100 Mallett St
Camperdown, NSW 2050

Phone:  +61-2-9351 0799 or 0789
Fax:    +61-2-9351-0652
E-mail: jgoetz@med.usyd.edu.au

 contact | research | publications


  Phosphatase 2A (PP2A) is a multimeric enzyme, containing a catalytic and a structural component associated with a large number of regulatory subunits. PP2A exerts a wide range of cellular effects including regulation of the cell cycle and cell fate determination during development. Studies aimed at attributing specific functions to PP2A are hampered by the fact that phosphatase inhibitors like okadaic acid are not completely specific. In order to understand the in vivo role of PP2A and to identify the in vivo substrates, we are applying a transgenic approach which is more effective because PP2A can be controlled in a time- and tissue-specific manner.

  We are especially interested in the role of PP2A in the brain, where in addition to heart the highest levels of PP2A are found. PP2A has been shown to be associated with both microtubules and neurofilaments and to dephosphorylate in vitro both neurofilaments and tau (a microtubule-associated protein). Hyperphosphorylated tau protein is the principal constituent of neuro-fibrillary lesions in Alzheimer's disease. Hallmarks of ALS (Amyotrophic Lateral Sclerosis) pathology include neurofilament inclusions and altered neurofilament phosphorylation.

  As a first step, we have generated mice lacking the major catalytic isoform of PP2A, Ca. Mice homozygous for the mutant allele die in utero at the onset of gastrulation. The mechanisms underlying early lethality are currently investigated.

  In order to assess the role of PP2A in neurons we have started to develop two alternative strategies :

(A)  A brain-specific knockout of PP2A is achieved by producing a mouse strain carrying a lox-flanked Ca gene which will be mated to a mouse strain expressing cre recombinase exclusively in neurons. Cre expression will be driven by a promoter which is turned on late in development! Most likely, by this approach embryonic or early lethality due to the absence of PP2A in the periphery or during early neuronal development will be prevented. When applicable, the lox-flanked Ca mice can be used to achieve a tissue-specific knockout in organs other than the brain.

(B)  The Ca homozygous knockout mice will be rescued using the binary tetracycline-transactivator system. An HA (hemagglutinin)-tagged version of Ca is expressed under the control of a tetracycline-sensitive transactivator. Upon feeding of tetracycline at any postembryonic stage, a null phenotype can be induced and eventually reverted. We plan to establish primary neuronal cultures where tetracycline can be added and removed from the culture medium ad libitum.

 contact | research | publications

Recent publications

D.Shmerling et al. (1998). Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93, 203-214
J.Götz et al. (1998). Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Ca. PNAS 95, 12370-12375
Götz et al. (1995) EMBO J 14, 1304
Goedert et al. (1995) In: Recent Advances in Alzheimer's Disease and
Related Disorders (1995), chapter 54: 493
Goedert et al.(1995) Biochem.Soc.Transact. 23, 80
Goedert et al. (1995) Neurobiol. of Aging 16, 325
Li et al. (1996) Proc.Natl.Acad.Sci.USA 93, 6158

Last updated: 2/24/99- Thomas Gutjahr

Institute of Molecular Biology © Institute of Molecular Life Sciences, University of Zürich,
maintained by // last modified 29.12.2009