Spreading of α‑synuclein (α-Syn) aggregates in the brain plays a key role in the early phase of Parkinson’s disease (PD). While several preclinical models of synucleinopathies have been developed for studying the neurotoxicity of prion-like α-Syn aggregate spreading, they remain to be systematically explored with regards to early pathological events that could be targeted to delay or prevent progression of PD. Using 3D whole-brain light sheet fluorescence microscopy (LSFM), we will show an ongoing study that aims to provide detailed spatiotemporal insight into the transmission of misfolded α-Syn in a α-Syn pre-formed fibril (PFF) mouse model of PD. C57BL/6 male mice received two unilateral intrastriatal injections of mouse α-Syn PFFs (mPFFs from StressMarq). Mice were terminated at 1-, 4-, 8-, and 12-weeks post injection, and brains were immunolabelled for α-Syn phosphorylated at serine-129, cleared, and scanned using LSFM. Using a deep-learning computational analysis it is possible to map whole-brain pathological α-Syn architecture at a cellular resolution to reveal distinct stages of α-Syn aggregate spreading and toxicity in a neural circuit-dependent manner.

Learning Objectives:

1. Review the basic principle of 3D microscopy.

2. Recognize the pathophysiology of Parkinson disease.

3. Demonstrate knowledge on how alpha-synuclein aggregates spread across the brain.