Here, we took advantage of well-defined mouse models for α-synucleinopathy (A30P-αS ) to explore proteome changes in the cerebrospinal fluid which are related to these distinct proteopathic lesions. Non-targeted liquid chromatography-mass spectrometry revealed that the majority of proteins that undergo age- and disease-related changes in either mouse model was linked to microglia, and more specifically to previously described disease state-specific microglia transcriptomic signatures. The finding that such transcriptomic changes translate into corresponding protein changes in cerebrospinal fluid is of high clinical relevance, supporting efforts to identify bodily fluid biomarkers that reflect the various functional states of microglial activation in Parkinson’s disease.