Genetically encoded fluorescent reporters to visualize α-synuclein pathology in live brain
Summary
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 α-synuclein (α-Syn) inclusions in live brain 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 5-fold increase in fluorescence upon incorpor
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# Genetically encoded fluorescent reporters to visualize α-synuclein pathology in live brain
*Published: 2026 Apr 2*
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
α-synuclein (α-Syn) inclusions in live brain 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 5-fold increase in fluorescence upon incorporation into α-Syn
inclusions. They reliably reflected α-Syn 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 inclusions on neuronal
activity and synaptic function. They could be selectively targeted to specific
neuronal subtypes, facilitating measurement of the pathological effects on
transcriptomes and metabolomes at the single-cell level. In live-cell imaging,
the reporters helped identify inhibitors of α-Syn inclusion formation.
Collectively, these genetically encoded reporters support multiple applications
to study α-Syn inclusions in live brain.
DOI: 10.1016/j.cell.2026.01.035