Project No.2489

Primary Supervisor

Dr Chrisostomos Prodromou –  University of Sussex

Co-Supervisor(s)

Dr Mathias Baud – University of Southampton

Prof Laszlo Vigh, Institute of Biochemistry, Biological Research Centre, LipidArt (Industry partner)

Dr Zslot Torok, Institute of Biochemistry, Biological Research Centre, LipidArt (Industry partner)

Prof John Spencer – University of Sussex

Dr. Mark S. Roe – University of Sussex

Summary

Rationale and importance

With 50 million global cases of Alzheimer’s disease (AD) and care costs of 1 trillion UK pounds (expected to triple by 2050), there is a pressing need to slow disease progression, sustain productive lives and reduce costs. Dihydropyridines, like LA1011, are used for hypertension.

However, we have shown that LA1011 eliminates neurodegeneration in an AD mouse model and identified the Hsp90-FKBP51 complex as the molecular target. Senile plaques in the brain elevate FKBP51 leading to tau pathology, a process regulated by the Hsp90-FKBP51 complex. We have determined the structure of a Hsp90-LA1011 co-complex and shown that LA1011 competes with FKBP51 for binding to Hsp90. Our results suggest that LA1011 may help to restore normal levels of FKBP51-Hsp 90 complex in AD cells, which consequently reduces tau pathology.

Approaches to be used

Our aims are straightforward and threefold. A). A structure based design of LA1011 to improve Hsp90 binding. B). Using biochemical, biophysical and cellular approaches, we will evaluate the importance of FKBP51 and other cochaperones (Aha1, FKBP52 etc) involved in the phosphorylation of Tau, which also compete with LA1011 for Hsp90 binding. C). LipidArt are uniquely placed to investigate whether LA1011 alters the membrane physical state, organization and effects on the lipidom and cause the co-induction effect of LA1011. This is a very relevant question since FKBP51 is involved in adipogenesis and lipid metabolism.

Areas of potential impact

There is potential that full AD onset could be prevented by developing LA1011. LA1011 may be applicable to other chaperone dependant neurodegenerative diseases. LA1011 is a useful reagent for use to better understand the complex nature of the Hsp90 mechanism per se, but also in the context of a variety of other diseases (from inflammation to cancer). The project offers an excellent multidisciplinary training opportunity.

Candidate qualities

Experience in either cellular or structural biology is desirable.