A topographical atlas of -synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neurodegeneration. Lewy pathology contains aggregated alpha-synuclein (alpha Syn), a protein encoded by the SNCA gene which is also mutated or duplicated in a subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for the protein results in a diffuse reactivity pattern, providing little insight into the types of cells expressing alpha Syn. As a result, insight into alpha Syn expression-driven cellular vulnerability has been difficult to ascertain. Using a combination of knock-in mice that target alpha Syn to the nucleus (SncaNLS) and in situ hybridization of Snca in wild-type mice, we systematically mapped the topography and cell types expressing alpha Syn in the mouse brain, spinal cord, retina, and gut. We find a high degree of correlation between alpha Syn protein and RNA levels and further identify cell types with low and high alpha Syn content. We also find high alpha Syn expression in neurons, particularly those involved in PD, and to a lower extent in non-neuronal cell types, notably those of oligodendrocyte lineage, which are relevant to multiple system atrophy pathogenesis. Surprisingly, we also found that alpha Syn is relatively absent from select neuron types, e.g., ChAT-positive motor neurons, whereas enteric neurons universally express some degree of alpha Syn. Together, this integrated atlas provides insight into the cellular topography of alpha Syn, and provides a quantitative map to test hypotheses about the role of alpha Syn in network vulnerability, and thus serves investigations into PD pathogenesis and other alpha-synucleinopathies.