GASTRO-PD · Investigating non-motor symptoms of Parkinson’s Disease using Drosophila melanogaster as model

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Project objective

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms (MS). PD is also characterized by the largely understudied non-motor symptoms (NMS). Gastrointestinal (GI) symptoms are one of the most common NMS and appear up to ten years before MS’ insurgence, affecting patients’ quality of life and participating to healthcare costs. The GI tract has a pivotal role in regulating body’s physiology and pathology partly via the “brain-gut axis”, the communication route between the gut and the brain. Studying how the gut and the gut-brain axis influence GI NMS in PD is challenging in mammals due to the anatomical complexity and limited understanding of gut–brain communication. To overcome these limitations, I will use the model organism Drosophila melanogaster. Drosophila shares similarities in gut cell composition and signaling pathways and provides sophisticated genetic tools to allow spatiotemporal control of gene expression. I will investigate how impairment of PD–associated genes result in GI phenotypes characteristic of the disorder. I will focus on how mutations of alpha-synuclein and Pink1 genes influence gut physiology, neuronal degeneration and mitochondrial function. My results in flies show that human A53T alpha-synuclein overexpression and Pink1 null mutants exhibit a constipation-like phenotype in female flies, in line with what seen in human patients. Building on these data I aim to 1) explore the role of modulators of alpha-synuclein for NMS appearance in the gut and in the brain; 2) identify the cellular nature (in the gut or in the brain) of NMS’ insurgence; 3) elucidate the timeline of mitochondrial dysfunction appearance in the enteric epithelial cells and dopaminergic neurons. I will address these questions using the power of Drosophila genetics, behavior and physiology. Ongoing work in the host laboratories on inter-organ communication and mitochondrial physiology will nicely complement the scope of the project.

Original text from CORDIS.

Participants

• INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE · ParisCoordinatorFrance

Links

• View on CORDIS
• DOI: 10.3030/101274495