Project title: The role of ER-mitochondria tethering and calcium transfer in neurodegeneration

Project supervisor: Dr Alex Whitworth (BMS & CDBG)

Application deadline: Friday 14 December 2012.

Project description

The transfer of calcium between ER and mitochondria is an essential function in cellular homeostasis. Recent studies have identified several proteins that mediate ER-mitochondria tethering to promote calcium exchange, e.g. mammalian Mfn2 (de Brito and Scorrano 2008) and the yeast homolog of Miro (Kornmann et al. 2011). Mutations in Mfn2 have previously been linked to motor-neuron degeneration in Charcot-Marie-Tooth type 2A suggesting a possible link between ER-mitochondria cross-talk and neurodegeneration. In addition, investigations into other factors linked to Parkinson’s disease, PINK1 and parkin, implicate regulation of Miro by PINK1/parkin (Wang et al., 2011) further substantiating a possible link between ER-mitochondria tethering and neurodegeneration.

Much is still be learned about the role of ER-mitochondria tethering in neuronal homeostasis – where, when and how this happens. In this project we will use a combination of techniques, primarily using the powerful genetic approaches in Drosophila coupled with cutting edge live-imaging techniques to analyse the effects of manipulating ER-mitochondria tethering and calcium transfer upon neuronal function and survival.

References:

• de Brito OM and Scorrano L (2008).
  "Mitofusin 2 tethers endoplasmic reticulum to mitochondria."
  Nature 456 (7222): 605-10.
• Kornmann B, et al. (2011).
  "The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections."
  Proc Natl Acad Sci U S A 108 (34): 14151-6.
• Wang X, et al. (2011).
  PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility.
  Cell. 147(4):893-906.

This project is available to start Spring 2013 or Autumn 2013, and is open to UK and EU students. International students may also apply but the higher fee status will need to be covered by additional funds or competitive award of a fee waiver.

Contact Details:

Dr Alex Whitworth

Web: http://www.shef.ac.uk/bms/research/whitworth

Email: a.whitworth@sheffield.ac.uk