α-Synuclein aggregation is implicated in several neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy Bodies (DLB). Changes in cellular signaling pathways induced by this aggregation may contribute to cell death and disease pathogenesis. To investigate this, we used quantitative proteomics to measure the relative abundance changes of the proteome and phosphoproteome in response to aggregation of endogenous α-synuclein in the brain of a mouse model. Aggregation in this model is induced by the intrastriatal injection of α-synuclein pre-formed fibrils and recapitulates several cardinal features of human PD, including progressive aggregation concomitant with dopaminergic degeneration and motor symptoms. We quantified the relative abundance changes of 5,290 proteins and 2,763 phosphosites in wildtype mice and found significant changes in vesicle-mediated transport, RNA processing and the immune response. The immunoproteasome, an altered form of the constitutive proteasome that is induced in response to stress, was elevated in response to α-synuclein aggregation. Increased levels and activity of the immunoproteasome were found in human DLB compared with age-matched healthy controls. Additionally, the immunoproteasome degrades α-synuclein fibrils more efficiently than the constitutive proteasome. This is the first documented role of the immunoproteasome in synucleinopathies.