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Investigating the physiological function of the amyloid precursor protein in Drosophila melanogaster

Thesis

English

<10670/1.r9anxv>

Abstract

The amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein from C. elegans to humans. It has mainly been known and studied for its implication in Alzheimer’s disease (AD) because one of its proteolytic products, the Aβ oligomers, aggregates and forms senile plaques observed in the brain of AD patients. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). The general introduction of this thesis summarizes all previous findings on the implication of APP and APPL in various aspects of neuron biology, highlighting the need for further investigation on their overarching function and molecular underpinnings. We hypothesized that APP might be involved in a homeostasis mechanism maintaining neuronal health and counteracting perturbations throughout ageing. In the first chapter, we report that APPL loss of function results in the dysregulation of endolysosomal function in both neurons and glia. We observed a notable enlargement of early endosomal compartments in neurons followed by the accumulation of dead neurons in the brain during a critical period at a young age and subsequent reduction in lifespan. These defects can be rescued by reducing the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show, for the first time, that the secreted extracellular domain of APPL interacts with glia, regulates their endosomal morphology and this is necessary and sufficient for the clearance of neuronal debris in an axotomy model. We propose that the APP proteins represent a novel family of neuro-glial signaling proteins required for adult brain homeostasis. The second chapter describes a collaborative project, where we performed the RNAi screening of potential Parkinson’s disease (PD) candidate genes. We identified two autosomal recessive mutations found on PD families that cause a locomotion defect in fruit flies and, in the future, we will investigate further their implication in dopaminergic neurons.

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