PhD Studentship: Investigation of the role of ER-mitochondria interactions in neurodegeneration and

A large body of evidence implicates endoplasmic reticulum (ER) stress and damage to mitochondria in the pathogenesis of neurodegenerative diseases. However, the upstream causes of ER stress or mitochondrial damage remain to be determined and how mutations in non-ER and non-mitochondria proteins that cause disease elicit ER stress and mitochondrial dysfunction is a conundrum. Similarly, the mechanisms linking these apparently disparate insults are unclear.

We have shown recently that compromised mitochondria-associated membranes (MAM) function is implicated in familial amyotrophic lateral sclerosis (ALS) (De Vos et al., 2012; Morotz et al., 2012; Stoica et al., 2014; Stoica et al., 2016). MAM is a specialised ER domain that is in close contact with mitochondria and is involved in “house-keeping” functions such as calcium homeostasis and lipid metabolism, but also has been linked to ER stress, mitochondrial (dys)function, and apoptosis (Hayashi et al., 2009).

The aim of this project is to investigate how compromised MAM function contributes to ER stress and mitochondrial damage in models of neurodegeneration and to explore the underlying molecular events.

This research will involve techniques such as advanced quantitative microscopy including time-lapse, confocal and super-resolution microscopy, CRISPR/CAS9 gene editing technology, western blotting and recombinant DNA technology and use cell lines, iPSC, primary neurons and zebrafish as model systems.

Funding Notes

The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.

References

References:
• De Vos, K.J., Morotz, G.M., Stoica, R., Tudor, E.L., Lau, K.F., Ackerley, S., Warley, A., Shaw, C.E., and Miller, C.C. (2012). VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet 21, 1299-1311.
• Hayashi, T., Rizzuto, R., Hajnoczky, G., and Su, T.P. (2009). MAM: more than just a housekeeper. Trends Cell Biol 19, 81-88.
• Morotz, G.M., De Vos, K.J., Vagnoni, A., Ackerley, S., Shaw, C.E., and Miller, C.C. (2012). Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet 21, 1979-1988.