Role of the ER/Mitochondria interface in Alzheimer’s disease
University of Sheffield - Neuroscience
|Funding for:||UK Students, EU Students, Self-funded Students|
|Funding amount:||Home/EU fee and RCUK rate stipend for three years|
|Placed on:||7th November 2016|
|Closes:||1st February 2017|
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The aim of this project is to investigate the role of the ER/Mitochondria interface in Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common form of dementia. Although most cases of AD are sporadic, in about 1% of patients the disease is inherited as a result of mutations in one of three genes: the amyloid precursor protein (APP) gene, and the presenilin genes PSEN1 (presenilin-1) and PSEN2 (presenilin-2). Clinically, these familial AD cases are similar to the sporadic cases but usually with an earlier age of onset and more aggressive disease.
While mutations in APP, PSEN1 and PSEN2 explain much of the genetic cause of early onset AD, this has not yet led to significant advances in treatments. The cause of Aß deposition in the more common sporadic late-onset AD is even less clear and further from therapeutic interventions. One genetic risk factor that has consistently been associated with late-onset AD is the E4 allele of apolipoprotein E (APOE4). The mechanism by which APOE4 increases the risk to develop AD may involve APP metabolism but the exact details are not known.
Recent evidence from our lab and others have uncovered that disruption of the ER/mitochondria interface is a common feature in neurodegenerative diseases including AD (1-3). In this project we will investigate the ER/mitochondria interface and its involvement in familial and sporadic AD.
This research will involve advanced techniques such as quantitative microscopy including time-lapse, confocal, and super-resolution fluorescence microscopy of mitochondrial, ER and vesicle dynamics and transport, CRISPR/Cas9 gene editing, and stem cell technology. Models systems will include cell lines, primary neurons and AD patient-derived iNeurons and iAstrocytes (4).
The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.
Proposed start date: October 2017
(1) Stoica, R., et al. (2014). ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun, DOI:10.1038/ncomms4996.
(2) De Vos, K. J., et al. (2012). VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet, DOI:10.1093/hmg/ddr559
(3) Area-Gomez, E., et al. (2012). Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J, DOI:10.1038/emboj.2012.202
(4) Meyer, K., Ferraiuolo, L. et al. (2014). Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A, DOI:10.1073/pnas.1314085111
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