[Historical Versions Pending Deletion] Multiscale brain-wide mapping of α-synuclein-driven dopaminergic degeneration and white matter impairment in α-synucleinopathy mice

ABSTRACT: Citation: [Multi-modal imaging analysis of Parkinsonian mice reveals region-specific alterations in the substantia nigra] The spatiotemporal relationships among α-synuclein inclusion formation, dopaminergic degeneration, and white matter microstructural changes remain poorly defined. To address this, we unilaterally injected preformed fibrils (PFFs) or monomeric α-synuclein into the substantia nigra pars compacta (SNc) of wild-type mice. At 12 and 20 weeks post-injection (wpi), we performed ex vivo magnetic resonance imaging (MRI) at 9.4T to assess microstructural, volumetric and paramagnetic changes, along with light-sheet microscopy (LSM) to map α- synuclein aggregates, and dopaminergic neuron at single-cell resolution across the whole brain. We developed a Python-based, automated registration pipeline that achieves <40 µm alignment error between ex vivo MRI and LSM and computes clearing-induced distortion, enabling scalable deformation analysis and multimodal multiscale data integration. Unilateral SNc injection of α-syn PFFs induced dense phospho-α-syn pathology in the ipsilateral SNc at 12 wpi, which decreased by 20 wpi in parallel with the loss of tyrosine hydroxylasepositive dopaminergic neuron. Pathogenic α-synuclein spreads along with dopaminergic denervation in the nigrostriatal pathway to the ipsilateral striatum and contralateral SNc. Our ex vivo MRI-LSM platform provides a scalable, open-source framework for understanding circuit-level and whole-brain propagation of pathology in an α-synucleinopathy model and beyond.

SUBMITTER: Benjamin F. Combes 

PROVIDER: S-BIAD3402 | bioimages |

REPOSITORIES: bioimages