Alpha-synuclein negatively controls cell proliferation in dopaminergic neurons

As researchers grapple with the mechanisms and implications of alpha-synuclein (α-syn) in neuropathology, it is often forgotten that the function(s) of α-syn in healthy cells remain largely elusive. Previous work has relied on observing α-syn localization in the cell or using knockout mouse models. Here, we address the specific role of α-syn in human dopaminergic neurons by disrupting its gene (SNCA) in the human dopaminergic neuron cell line, LUHMES. SNCA-null cells were able to differentiate grossly normally and showed modest effects on gene expression. The effects on gene expression were monodirectional, resulting primarily in the significant decrease of expression for 401 genes, implicating them as direct, or indirect positive targets of α-syn. Gene ontological analysis of these genes showed enrichment in terms associated with proliferation, differentiation, and synapse activity. These results add to the tapestry of α-syn biological functions. SIGNIFICANCE STATEMENT: The normal functions of α-syn have remained controversial, despite its clear importance in Parkinson's Disease pathology, where it accumulates in Lewy bodies and contributes to neurodegeneration. Its name implies synaptic and nuclear functions, but how it participates at these locations has not been resolved. Via knock-out experiments in dopaminergic neurons, we implicate α-syn as a functional participant in synapse activity and in proliferation/differentiation, the latter being novel and provide insight into α-syn's role in neuronal development.