Soluble α-synuclein oligomers drive transient corticostriatal pathology and delayed nigral vulnerability in a mouse model of early α-synucleinopathy.

α-Synucleinopathies display pronounced heterogeneity in the spatial distribution of α-synuclein (αSyn) pathology and clinical progression. Although distinct αSyn assemblies-from monomers and soluble oligomers to fibrils-exert non-equivalent biological effects, in vivo studies have predominantly focused on preformed fibrils (PFFs), leaving the pathogenic potential of soluble oligomers insufficiently explored. Here, we investigated the spatiotemporal, molecular, and behavioral consequences of striatal delivery of structurally validated αSyn oligomers in adult mice. Three-month-old male C57BL/6 J mice received bilateral injections of αSyn oligomers into the dorsal caudate-putamen and were analyzed at 30, 90, and 180 days post-injection (dpi) using molecular, histological, and behavioral approaches. αSyn oligomers induced a highly dynamic and region-specific pathological cascade. At 30 dpi, widespread inclusions were evident in cortical and limbic regions projecting to the striatum, followed by a progressive redistribution of pathology toward the striatum at later stages, while inclusions were consistently absent from the substantia nigra pars compacta. In parallel, αSyn oligomers elicited distinct spatiotemporal patterns of inflammatory and oxidative responses across brain regions, characterized by an immediate pro-inflammatory cytokine surge in the striatum, early but transient oxidative response in the cortex and delayed, sustained oxidative stress in the midbrain. Despite modest nigrostriatal degeneration and preserved gross motor performance, sensitive behavioral measures revealed early and persistent motor weakness, suggesting synaptic and axonal dysfunction rather than neuronal loss. Collectively, our findings provide the first in vivo evidence that soluble αSyn oligomers act as potent yet transient drivers of a distributed and partially reversible neuropathological program fundamentally distinct from canonical PFF-based models. By uncovering an oligomer-specific mode of αSyn-induced neurodegeneration, this work demonstrates that disease-relevant pathology can arise from dynamic, regionally uncoupled processes rather than stable fibrillar inclusions, redefining early α-synucleinopathy as a state of selective circuit vulnerability and revealing a previously unrecognized therapeutic window for intervention.