Praschberger, R., Kuenen, S., Schoovaerts, N., Kaempf, N., Singh, J., Janssens, J., Swerts, J., Nachman, E., Calatayud, C., Aerts, S., Poovathingal, S., Verstreken, P. (2023). Neuronal identity defines α-synuclein and tau toxicity.  Neuron 111(10): 1577--1590.e11.

FBrf0256553

Research paper

Pathogenic α-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 α-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 α-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of α-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 α-synuclein or tau. By uncovering synapse- and Ca[2+] homeostasis-related genes as tau toxicity modifiers, our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.

PMC10191620 (PMC) (EuropePMC)