| First Author | Zhang L | Year | 2026 |
| Journal | Cell | Volume | 189 |
| Issue | 7 | Pages | 2108-2127.e21 |
| PubMed ID | 41785852 | Mgi Jnum | J:383651 |
| Mgi Id | MGI:8320497 | Doi | 10.1016/j.cell.2026.01.035 |
| Citation | Zhang L, et al. (2026) Genetically encoded fluorescent reporters to visualize alpha-synuclein pathology in live brain. Cell 189(7):2108-2127.e21 |
| abstractText | Lewy bodies, a pathological hallmark of Parkinson's disease, are alpha-synuclein-enriched cytoplasmic inclusions that drive progressive neurodegeneration. A long-standing yet unmet goal has been the visualization of alpha-synuclein (alpha-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 alpha-Syn inclusions. They reliably reflected alpha-Syn inclusion propagation in the cortex of awake mice. Coupled with Ca(2+) 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 alpha-Syn inclusion formation. Collectively, these genetically encoded reporters support multiple applications to study alpha-Syn inclusions in live brain. |
