Role of the neddylation process in brain ageing

Ageing is the greatest risk factor for cognitive decline and neurodegeneration. A characteristic of ageing is the loss of proteostasis. Neddylation maintains proteome homeostasis, it is involved in neuronal differentiation and its deregulation is linked to neurodegenerative diseases. The role and mechanisms of Neddylation with physiological ageing remain still unclear.We studied the expression and impact of neddylation on ageing and cognitive decline. We found that neddylation increases with age in the hippocampus neurogenic niche both in human and mouse samples. Aged, but not young, Nae1+/- heterozygous mice present a reduction in cognitive activity. Different OMICS started to unravel cell types and biological processes altered by neddylation regulation in the hippocampus neurogenic niche. Firstly, single cell RNAseq deciphered a smaller number of radial glial, ependymal and pyramidal cells on aged Nae1+/- mice. Moreover, proteomic analysis showed enrichment on markers of astrocytes and microglia as well as deregulation of autophagy. These results provide new insights into the role of neddylation in age-associated cognitive decline as reveal novel cell types and biological processes altered as consequence of its deregulation with ageing.