Abstract: Lewy bodies, a pathological hallmark of Parkinson’s disease, are α-synuclein-enriched cytoplasmic inclusions that drive progressive neurodegeneration. A long-standing yet unmet goal has been the visualization of these inclusions in live brains and measurements of their pathological effects on individual neurons. Here, we developed genetically encoded reporters and knock-in mouse lines to achieve this goal. The reporters exhibited a 6-fold increase in fluorescence upon incorporation into α-synuclein inclusions. They reliably reflected α-synuclein inclusion propagation in the cortex of awake mice. Coupled with Ca2+ imaging and whole-cell recording, the reporters enabled measurement of the pathological effects of α-synuclein inclusions on neuronal activity and synaptic function. They can be selectively targeted to specific neuronal subtypes, facilitating measuring pathological effects on transcriptomes and metabolomes at the single-cell level. Overall, these reporters provide an opportunity to directly visualize α-synuclein inclusions in live brains and support various applications for measuring their pathological effects on individual neurons.