NeuralCipher Research overview
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Abstract Parkinson’s 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 parenchymal reactivity, 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 mapped 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 content. As expected, 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, which are relevant to the pathogenesis of multiple system atrophy. Surprisingly, we also find that ⍺Syn is relatively absent from select neuronal clusters, e.g., ChAT-positive motor neurons, whereas enteric neurons universally express some degree of ⍺Syn. We also present a web-based platform allowing for user-friendly interrogation of these results. Taken together, this integrated atlas provides much-needed insight into the cellular topography of ⍺Syn, and provides a quantitative map to test hypotheses about the role of ⍺Syn in network vulnerability, and thus serves investigations into PD pathogenesis and other αSynucleinopathies.
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