Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are defined by pathological alpha-synuclein (αSyn) aggregation.
• The M83 transgenic mouse model, while used for synucleinopathy studies, exhibits an aggressive phenotype.
• Investigating alternative models is crucial for understanding disease mechanisms.

Purpose of the Study:

• To evaluate the utility of wild-type (WT) mice injected with mouse αSyn preformed fibrils (PFFs) as an alternative model.
• To generate and characterize novel humanized αSyn mouse models for studying synucleinopathies.
• To compare the pathological and behavioral outcomes of different αSyn models.

Main Methods:

• Analysis of M83 mice using light-sheet microscopy.
• Injection of WT mice with mouse αSyn PFFs or PBS, followed by behavioral assessments (cognitive, motor).
• Generation of humanized αSyn mouse models (WT, A53T, E83Q) using CRISPR-Cas9 technology.

Main Results:

• M83 mice showed early cognitive deficits and significant spinal cord αSyn phosphorylation, correlating with motor deficits.
• WT mice injected with mouse αSyn PFFs exhibited minimal αSyn pathology and only mild motor deficits in males.
• Humanized models confirmed comparable human αSyn expression levels and detected phosphorylated αSyn in mutant lines.

Conclusions:

• Both M83 and WT αSyn PFF models have limitations for synucleinopathy research.
• Humanized WT, A53T, and E83Q SNCA models offer more physiologically relevant αSyn expression.
• These humanized models are expected to improve the reliability of synucleinopathy studies and aid in identifying therapeutic targets.