RNF10 moves from the synapse – where it interacts with a subunit of NMDA receptors – to the nucleus, to affect transcription by an unknown mechanism. As a result, Meox-2 is affected, and this is important as Meox-2 is reduced in Alzheimer disease (AD) patients in the literature, and Meox-2 mutation is ‘associated with AD’.
Preliminary data indicate RNF10 is down regulated in the Alzheimer disease brain, at least in late stages of the disease. Thus, the project is to investigate the role of long-distance signalling, from synapse to nucleus in AD pathogenesis, via RNF10; and to focus on early disease stages, noting that no changes in RNF10 cellular distribution are seen before pathology in the APP/PS1 mouse model, but changes are seen in the hippocampus as cognitive changes become measurable at 6 months of age.
Experimentally, Abeta oligomers can induce the movement of RNF10 to the nucleus and, in part using this system, the project aims to understand the mechanism of translation and subsequent mitochondrial impairment. Much of this work would take place in the APP/PS1 mouse model, which is a well-known and appropriate resource for AD research. Remarkably, preliminary data show RNF10 silencing in the APP/PS1 hippocampus restores cognition at 6 months of age.
Human iPSCs from AD patients would also be used, although with all studies of iPSCs variability between and within lines may be an issue, addressed by multiple biological and technical replicates, and noting sex and any other variables that may turn out to be relevant.
The second aim is, perfectly reasonably, to learn more of RNF10 target genes/proteins by established techniques such as ChiP sequencing and proximity labelling assays.