Neuronal identity defines a-synuclein and tau toxicity

Pathogenic -synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels is an open question. Here, we explore cell-type specific -synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to -synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of -synuclein or tau expression levels. Comparing vulnerable with resilient neurons enabled us to identify molecular signatures associated with these differential responses. We used these to verify, and then predict resilient and vulnerable neuron subtypes in human brains. This confirms substantia nigra dopaminergic neurons to be sensitive to -synuclein, and we predict pathogenic tau vulnerable and protected cortical neuron subtypes. Our work indicates that cellular determinants confer selective vulnerability to specific types of amyloid toxicity, thus paving the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.