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

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models representing various forms of familial Parkinsonism and conducted single-cell RNA sequencing on young entire brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients recapitulates these finding. Indeed, these disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Our research uncovers that one of the earliest indicators of disease in 5 different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons, and it suggests common synaptic molecular pathways contribute to the development of hyposmia. ### Competing Interest Statement The authors have declared no competing interest. * DAN : Dopaminergic neurons DEG : Differential expressed genes ERG : Electroretinograms KC : Kenyon cells Nac : Nucleus accumbens NBM : Nucleus basalis meynert OPN : Olfactory projection neurons PD : Parkinson’s disease Put : Putamen SING : Startle induced negative geotaxis