It has been hypothesized that the spread of misfolded proteins underlies patterns of neurodegeneration. Using a highly sensitive detection method, Alibhai et al. observed widespread early distribution of prion protein 'seeds' in a mouse model of prion disease but no correlation between the regions affected and subsequent patterns of neurodegeneration. Transcriptional analysis indicated distinct microglial responses to disease in brain regions that undergo neurodegeneration versus those that do not, suggesting that the host response to misfolded protein seeds determines subsequent pathology.