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Roles of SUMO proteases in Alzheimer’s disease

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

SUMOylation is a post-translational modification that regulates multiple neuronal signalling cascades and its dysfunction is strongly implicated in many neurodegenerative diseases including Alzheimer’s disease (AD).

Although the processes of SUMOylation are intensively studied, the mechanisms and consequences of deSUMOylating synaptic substrate are almost entirely unexplored. DeSUMOylation is mediated by one of nine known SUMO proteases, the best characterised of which are the SENP family of isopeptidases. However, even for SENPs, the properties, regulation, specific targets and physiological roles remain largely unknown.

This PhD proposal sets out to characterise the distributions and activities of SUMO proteases in neurons and test the hypotheses that:

1) SUMO proteases are critical mediators of synaptic activity, synaptic plasticity and of cell responses to stress.

2) Dysregulation of substrate deSUMOylation may be an underlying causative factor in the dendritic spine regression, synaptic collapse, neuronal death and network failure in dementia.

There have been no studies investigating levels or activities of SUMO proteases in brain tissue samples from AD patients. Therefore, a core aim is to define how protein deSUMOylation is altered in human AD brain and animal models of dementia, and determine how this impacts on synaptic pathology in AD. The student will systematically compare the levels individual SUMO proteases, tau, phospho-tau, APP and A together with the levels and identities of SUMOylated proteins in frontal cortex from least twenty separate AD patients and matched control patients by quantitative Western blotting.

In parallel, we will use primary rat dispersed neuronal and brain slice culture models of degeneration. The student will use combinations of biolistic transfection and/or viral infection with RNAi approaches to define how manipulating SUMO proteases regulates synaptic integrity, function and plasticity in Aβ stressed conditions using multiple techniques including surface biotinylation assays, and live and fixed cell confocal imaging.

This work is timely and important because it will advance understanding of neuronal cell biology and disease through mechanistic insight into how SP function and dysfunction impacts on synaptic transmission and plasticity.

References

Henley JM, Craig TJ and Wilkinson KA Neuronal SUMOylation: Mechanisms, Physiology, and Roles in Neuronal Dysfunction (2014) Physiol. Rev. 94, 1249-1285. PMID: 25287864

Guo C, Hildick KL, Luo J, Dearden L, Wilkinson KA and Henley JM (2013) SENP3-mediated DeSUMOylation of dynamin-related protein 1 Promotes Cell Death Following Ischemia. EMBO J. 32(11) 1514-28. PMID: 23524851

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