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Amyotrophic lateral sclerosis (ALS) is a lethal, devastating motor neuron disorder for which there is no cure. Most forms of ALS are sporadic but approximately 10% are inherited (familial ALS; FALS) and mutations in a number of genes have now been shown to be causative for these familial forms. A large body of evidence implicates endoplasmic reticulum (ER) stress and damage to mitochondria in the pathogenesis of ALS. 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 ALS 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 ALS caused by a mutation in vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) (1, 2). MAM is a specialized 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 (3).
The aim of this project is to investigate how compromised MAM function contributes to ER stress and mitochondrial damage in models of familial ALS and to explore the underlying molecular events.
This research will involve mammalian and fly model systems and techniques such as advanced quantitative microscopy including time-lapse and confocal fluorescence microscopy of mitochondrial and ER dynamics and transport, siRNA technology, western blotting and recombinant DNA technology.
Funding Notes:
This research project is one of a number of projects in the department. It is in competition for funding with the other projects. Usually the project which receives the best applicant will be awarded the funding. The funding is available to citizens of a number of European countries (including the UK). In most cases this will include all EU nationals. However full funding may not be available to all applicants.
References:
1. G. M. Morotz et al., Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet, (Jan 17, 2012).
2. K. J. De Vos et al., VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet, (Nov 30, 2011).
3. T. Hayashi, R. Rizzuto, G. Hajnoczky, T. P. Su, MAM: more than just a housekeeper. Trends Cell Biol. 19, 81 (Feb, 2009).
Research Assessment Exercise (RAE) 2008 Results