New tools to study α-Syn inclusions in mouse brains

lab animal Research highlights Neurodegenerative disease https://doi.org/10.1038/s41684-026-01713-w New tools to study α-Syn inclusions in mouse brains Check for updates Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the brain accumulation of intraneural inclusions termed Lewy bodies, which main component is the misfolded α-synuclein (α-Syn) protein. Although previous studies have advanced our understanding of Lewy body pathology in PD, visualizing α-Syn propagation in the live brain remains challenging. A new study overcomes this barrier by developing genetically encoded α-Syn reporters and knock-in (KI) mice that enable the tracking of α-Syn propagation in the brain and the study of its effects on individual neurons. First, the researchers engineered seven α-Syn–fluorescent protein fusion reporters and screened them in neuronal cultures treated with α-Syn preformed fibrils (PFFs) to induce synucleinopathy. Among them, α-Syn6H-EGFP (and its tdTomato variant) most efficiency labeled α-Syn+ inclusions. Next, to validate these reporters in vivo, the researchers generated Snca-6H-EGFP and Snca-6H-tdT KI mice, in which the reporter cassette was inserted into the Snca locus that encodes α-Syn. The team injected PFF into the brain of the animals and confirmed that the reporters reliably labeled α-Syn+ inclusions in the affected brain regions. Finally, using two-photon imaging in awake KI mice, the researchers tracked α-Syn6H-EGFP+ inclusions over time after PFF injection, revealing their gradual spread across cortical areas. Further experiments revealed that, when combined with two-photon Ca2+ imaging, the reporter mice enabled the measurement of the α Syn-induced decrease in neuronal activity. The researchers also generated the RCL-Snca-6H-EGFP mouse line for Cre-dependent, cell-type-specific labeling of α-Syn+ inclusions, which allowed the analysis of inclusion-induced synaptic dysfunction and transcriptional and metabolic changes in defined neuronal subtypes. Together, these reporter systems provide powerful tools to further uncover the mechanisms driving neurodegeneration in α-Syn pathology. Alexandra Le Bras Original reference: Zhang, L. et al. Cell (2026) https://doi.org/10.1016/j.cell.2026.01.035 Now open for submissions For research that reaches beyond boundaries Communications Health is a new open access journal from Nature Portfolio which will publish high-quality, editorially selected and peer reviewed advances in all areas of public and global health research. Manuscripts will benefit from an easy submission process and fast decisions, rigorous and balanced peer review, and high Nature Portfolio editorial standards. Our mission: • Look for potential in every paper • Champion the work of specialists globally • Carry our communities’ voices further • Promote open science and accessibility nature.com/commshealth 06ML3 Lab Animal | Volume 55 | April 2026 | 105 105  (...truncated)