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Content archived on 2024-06-18

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

Final Report Summary - 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)

Ageing is, so far, the main recognized cause for neurodegenerative disorders, and with the ageing population progressing rapidly in many industrialized countries, the challenges that neurodegenerative diseases pose for our society will only increase. As a consequence of this, the identification of cellular mechanisms underlying increased neuronal vulnerability to cytotoxic stress in the old is of primary importance for understanding the brain ageing phenotype. The Adaptogene Project started therefore with the main goal to identify genes and/or cellular events which, directly or indirectly, can participate in neuronal weakening during physiological ageing and thus conferring increasing neuronal chronic susceptibility to cytotoxic stress. As a consequence of this, weakened neurons are eventually more predisposed to the development of neurodegenerative disorders (such as Alzheimer’s Disease, Parkinson’s Disease, Prion disorders, etc…). Hence, our aim was to identify a mechanism occurring during physiological brain ageing and how this could chronically weaken neurons, and render them more prone to the subsequent development of an age-related disease, eventually switching physiological ageing to a pahtological ageing phenotype. By taken advantage of publicly available datasets and by used a biocomputing approach, the host laboratory identified a subset of genes of potential interest for Alzheimer’s disease. We focused our attention on one of these genes, namely Mahogunin (MGRN1), for its already known biological link with other neurodegenerative diseases such as prion disorders, and for its role in cellular and neuronal protection. We identified that MGRN1 levels decrease with physiological ageing in the brain. Specifically, we identify that, with physiological ageing, MGRN1 relocalizes to neuronal nuclei, therefore leaving its cytosolic levels at minimum. We reasoned that, as a consequence of nuclear enrichment, the cytosolic depletion of MGRN1 occurring with ageing could diminish neuronal efficiency to counteract cytosolic toxic stress, and therefore be a bona fide event enhancing neuronal vulnerability to cytosolic toxic stress during physiological ageing. By taking advantages of neuronal coltures, proteomics facilities, use of modified lentiviral vectors and microscopy facilities, we carried out our investigation and identified that a biochemical modification occurring on MGRN1 protein, namely its mono-ubiquitination, is the triggering event for MGRN1 relocalization, and also discovered that this biochemical modification is directly induced by a conventional phenomenon occurring with ageing, i.e. proteasome function impairment. Importantly, we also showed that a direct intervention on the identified mechanism can, in turn, change neuronal physiology and capability to counteract age-associated stress. This is of great importance, as it can pave the way for a potential intervention aimed at increasing neuronal fitness to counteract age-associated stress.
This research can be therefore relevant for the society in the perspective of the comprehension, on one side, of how brain ageing is indeed a cellular and biochemical mechanism with its rule and processes; and in the perspective of potential intervention, on another side, on the identified mechanisms to give neuronal protection and, on a longer view, to provide a way to counteract age-associated neuronal dysfunction.




Contacts:
• Stefano Benvegnù: Centro de Biologia Molecular “Severo Ochoa”, calle Nicolas Cabrera 1, Laboratory 122, Campus de la Universidad Autónoma de Madrid – 28049 (Madrid - Spain). +34-911964520
• Carlos G. Dotti: Centro de Biologia Molecular “Severo Ochoa”, calle Nicolas Cabrera 1, Laboratory 122, Campus de la Universidad Autónoma de Madrid – 28049 (Madrid - Spain). +34-911964520