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

• DOI: 10.7554/elife.98348.2
• Publication Date: 2025-02-28T10:25:10Z
• Authors: Ulrike Pech; Jasper Janssens; Nils Schoovaerts; Sabine Kuenen; Carles Calatayud ...; Sandra F Gallego; Samira Makhzami; Gert Hulselmans; Suresh Poovathingal; Kristofer Davie; Adekunle T Bademosi; Jef Swerts; Sven Vilain; Stein Aerts; Patrik Verstreken

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to emergence issues, patients frequently experience non-motor symptoms, such as sense smell (hyposmia). cellular molecular bases for these early defects remain enigmatic. To explore this, we developed new collection five fruit fly models familial conducted single-cell RNA sequencing young brains models. Interestingly, cholinergic projection neurons most vulnerable cells genes associated with presynaptic function deregulated. Additional single nucleus three specific brain regions Parkinson’s disease confirms findings. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Correcting specifically interneurons flies or inducing signaling Parkinson mutant human induced vitro using nicotine, both rescue age-dependent neuron decline. Hence, our research uncovers one earliest indicators 5 different higher-order this contributes development hyposmia. Furthermore, shared pathways failure ultimately contribute later life.