A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery

Abstract

Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neuron loss. Lewy pathology contains aggregated Synuclein (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 diffuse signal, providing little insight into the types of cells expressing Syn. As a result, insight into Syn expression-driven cellular vulnerability has been difficult to ascertain. Using a combination of knock-in mice that target Syn to the nucleus of cells (SncaNLS) and in situ hybridization of Snca in wild-type mice, we systematically map the topography and cell types expressing Syn in the mouse brain, spinal cord, retina, and gut. We find a high degree of correlation between Syn protein and RNA levels across multiple brain regions and further identify cell types with low and high Syn. We found that Syn is highly expressed in neurons, particularly those involved in PD and to a lower extent in non-neuronal cell types, notably those of oligodendrocyte lineage. We also find that Syn is devoid in certain neuron types (e.g. ChAT-positive motor neurons), and that all enteric neurons express Syn to a certain degree. Taken together, this atlas provides much-needed insight into the cellular topography of Syn, and provides a quantitative map to test assumptions about the role of Syn in network vulnerability in PD and other Synucleinopathies.