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ERC

PAROSIN Report Summary

Project ID: 311394
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - PAROSIN (Protection against reactive oxygen species in neurodegeneration)

The overall aim of this project was to understand the functional significance of a family of proteins that are found in the nervous system. We had shown prior to this project that loss of one of these proteins in the mouse causes cell death in the part of the brain that controls co-ordination and movement, called the cerebellum. Interestingly, this protein (known as oxidation resistance 1, or OXR1) had also been shown to be important for protecting against unwanted damage by oxygen in cells, also known as oxidative stress. Interestingly, OXR1 is a member of a family of proteins that share a common protein region, or domain, called the TLDc domain. Therefore, in this project, the goal was to investigate the molecular function of OXR1 and other TLDc proteins in the nervous system, and understand how and why they could be protective against oxidative stress.

In Objective 1, we identified other proteins that interact with OXR1 and other TLDc proteins in cells and brain tissue. This has been a highly effective method for understanding the function of OXR1, and we discovered it modifies a protein that is important for motor neuron disease (TDP-43), a key enzyme that is essential for energy metabolism in the brain (GPI) and other already-established antioxidant proteins that we are continuing to study.
In Objective 2, it had been suggested that OXR1 was found in the mitochondria - key parts of the cell required for energy production. Here we established that OXR1 is found on the outside of mitochondria membranes and that disruption of OXR1 influences the structure of mitochondria in neuronal cells.
The focus of Objective 3 was on other members of the TLDc family, and we studied a mouse model where the related protein NCOA7 was disrupted. Interestingly, these mice did not share the same cell death in the brain as OXR1 mutant mice. In addition, we established that all members of the TLDc family could be protective against oxidative stress, and this relied on the TLDc domain itself being in place and unaltered. Importantly during the project, many new human mutations were discovered in the TLDc protein TBC1D24; these appear to cause a complex range of neurological disorders characterised by epilepsy and hearing loss. Therefore we began new collaborations to study the effect of human mutations on the function of TBC1D24; this work is currently on-going.
For Objective 4, our aim was to study OXR1 in human cell-lines, however access to these was more difficult than anticipated and therefore we were unable to complete our studies in this area.

In summary, this project has shed new light on the molecular function of TLDc proteins; this has particular significance given the discovery of an increasing number of human mutations in TBC1D24 in neurological disease; our discoveries will facilitate new studies into these disorders.

Reported by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
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