Neuronal identity defines a-synuclein and tau toxicity

Pathogenic a-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 remains elusive. Here, we explore cell-type-specific a-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 determine which cellular environments react most to a-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulner-ability independent of a-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic a-synuclein or tau. By uncovering synapse-and Ca2+ homeostasis-related genes as tau toxicity modifiers, our work paves the way to leverage neuronal identity to uncover modifiers of neurodegen-eration-associated toxic proteins.