The accumulation of cellular damage, including DNA damage, is hypothesized to contribute to ageing-related neurodegenerative changes. DNA excision repair cross-complementing group 1 (Ercc1) knockout mice represent an accepted model of neuronal ageing, showing gradual neurodegenerative changes, including loss of synaptic contacts and cell body shrinkage. Here, we used the Purkinje cell specific Ercc1 DNA-repair knockout mouse model to study ageing in the mouse Cerebellum. We performed an in-depth quantitative proteomics analysis, using stable isotope dimethyl labelling, to decipher changes in protein expression between the early (8 weeks), intermediate (16 weeks) and late (26 weeks) stages of the phenotypically ageing Ercc1 knock-out and healthy littermate control mice. The expression of over 5200 proteins from the cerebellum was compared quantitatively, whereby 79 proteins (i.e. 1.5%) were found to be substantially regulated during ageing. These molecular markers of the early ageing onset did nearly all belong to a strongly interconnected network involved in excitatory synaptic signalling. Using immunohistological staining we obtained temporal and spatial profiles of these markers confirming not only the proteomics data, but in addition revealed how the change in protein expression correlates to synaptic changes in the cerebellum. In summary, this study provides a highly comprehensive spatial- and temporal view of the dynamic changes in the cerebellum and Purkinje cell signalling in particular, indicating that synapse signalling is one of the first processes to be affected in this premature aging model, leading to neuron morphological changes, neuron degeneration, inflammation and ultimately behaviour disorders.