The road from physiological to pathological ageing
The EU-funded ADAPTOGENE (Functional evaluation of newly identified deregulated genes in Alzheimer's disease patients using neuronal cultures and mouse model of the disease, and possible contributions to prion disease) project has investigated the link between ageing and susceptibility of neurons to cytotoxic stress. Sifting through publicly available data sets and applying a biocomputing approach, the researchers identified a set of genes with potential links to Alzheimer's. One of the genes, mahogunin (MGRN1), has already been identified with prion disease and its neuronal protective role. ADAPTOGENE research showed that levels of the protein MGRN1 decrease with ageing and this is accompanied by relocalisation to neuronal nuclei reducing concentrations in the cytosol to a minimum. The researchers came to the conclusion that this could interfere with the ability of neurons to withstand cytotoxic stress. Backing this up, ADAPTOGENE researchers identified a modification of the MGRN1 protein that triggers relocalisation. Moreover, they showed that this biochemical change is due to a phenomenon common in the ageing brain, proteasome function impairment. Involving removal of unwanted proteins, the scientists demonstrated that direct intervention of this mechanism can change neuronal physiology and capability to counteract age-associated stress. Combination of genetic, cell and molecular approaches to the problems encountered in the ageing brain have provided details of just one mechanism responsible. This will no doubt open leads to early diagnosis and possible prevention of neurodegenerative diseases and general decline.
Keywords
Ageing, neurodegenerative disease, cytotoxic stress, Alzheimer's, prion disease, MGRN1
