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Project

Olfactory defects in Parkinson’s disease at single-cell resolution

Parkinson’s disease (PD) is a very common but incurable neurodegenerative disease. While motor defects are a hallmark of the disease, defects in sleep or the ability to smell are well-recognized nonmotor-related symptoms. These defects precede motor symptom onset by several years and may provide important clues about the earliest phases of PD. However, how the inbibition to smell (hyposmia) develops in PD, and which cells in the brain are responsible remain largely unanswered questions. In this proposal, we deploy a new collection of >80 knock-in fruit flies with PD pathogenic mutations to define the origin of hyposmia. The use of flies is warranted because olfactory circuits between flies and men are well conserved. Preliminary work also shows that like in humans, PD mutant flies show defects in olfactory perception. Here, we will use single-cell sequencing of all the cells of the brains of our mutants to (1) stratify the genetic space of PD by comparing mutants, and (2) define the cell types in the olfactory circuit that are most affected. We will also use imaging of neuronal activity of defined olfactory circuit neurons in living flies and resort to postmortem patient material to assess the evolutionary conservation. Our work not only has the capacity to directly link PD-causative genes to the regulation of olfaction, but it will also start to provide insight as to why these broadly-expressed PD-related genes affect specific neurons while leaving other neurons intact.

Date:1 Jan 2019 →  31 Dec 2022
Keywords:Medical cell biology
Disciplines:Rhinology