Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models

Abstract

The diagnosis of Parkinsonism is based on motor symptoms that are caused by reduced dopaminergic output. However, decades earlier, patients report non-motoric problems, including hyposmia. It is not known if non-motor and motor defects are causally connected. Using unbiased methods, we identified common synaptic defects in cholinergic neurons across premotor-stage familial fly Parkinson models and in patient samples. These early synaptic defects cause olfactory performance problems. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling onto Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Our approach reveals shared pathways of synaptic failure in cholinergic neurons that drive dopaminergic dysfunction across familial Parkinson models.

Spatial transcriptomics in the adultDrosophilabrain and body

“…To look at cell types, we made use of our annotated scRNA-seq atlas of the fly brain (Davie et al, 2018; Li et al, 2022; Pech et al, 2023). First, we checked the expression of C15 , acj6 , Oaz , caup and unpg , known markers for olfactory projection neurons (OPNs).…”