Title: Identification of novel modifiers of synaptic function, neurodegeneration and longevity in a Drosophila FTD/ALS model
Funder: The Academy of Medical Sciences

Abstract: The proposed project will employ a unique and powerful combination of a functional genetic screen and anatomical and behavioural analyses in the fruit-fly Drosophila to: a) Discover new genes that modify pathological synaptic phenotype in a Drosophila model of human frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS), and b) Identify the genes from (a) that have an additional effect on neurodegeneration and lifespan in FTD/ALS flies. Unlike the screens focusing on “morphological” (i.e. functionally irrelevant) phenotypes in various animal models of FTD/ALS, this project will reveal direct functional regulators of FTD/ALS synapses, likely to represent more effective therapeutic targets for treating FTD/ALS. An intronic repeat expansion in the C9ORF72 gene is the main genetic cause of FTD and ALS, two diseases with partially overlapping pathologies. Evidence points to synaptic dysfunction as the underlying cause of functional decline in several neurodegenerative disorders, including FTD/ALS. For example, the brains of FTD patients exhibit significant synaptic receptor loss and C9ORF72 accumulation, and pathological changes at the neuromuscular synapse of ALS patients characterise earliest symptoms of the disease. Overexpression of toxic C9ORF72 dipeptides in Drosophila mimics the most important clinical and neuropathological symptoms of FTD/ALS including reduced lifespan, neurodegeneration and impaired neuromuscular transmission. We will cross these “FTD/ALS flies” to individual deletion lines and analyse the progeny electrophysiologically to find the genes that “modify” the aberrant synaptic phenotype during development. This will be followed by behavioural and histological analyses to identify the genes that ameliorate reduced longevity and anatomical damage in adult FTD/ALS animals.

Lay abstract: Frontotemporal dementia (FTD), Alzheimer’s Disease and Lewy Body Dementia are the most common causes of human dementias. The major problem in developing treatments for these disorders is the lack of therapeutic targets. My proposal aims to correct this problem using a unique combination of sophisticated genetic, electrophysiological, anatomical and behavioural approaches. Cognitive impairment characterising dementias is likely caused by pathological changes in synapses, points of communication between nerve and other cells. These changes occur in early stages of dementias, providing a potential target for therapeutic interventions. FTD and Amyotrophic lateral sclerosis (ALS) are related diseases caused by mutations in the same gene (C9ORF72). While FTD is a progressive brain disease, ALS affects motoneurons controlling voluntary muscles. FTD/ALS can be successfully replicated in animal disease models. With its vast array of genetic tools, and synapses that are structurally and functionally similar to humans’, the fruit-fly Drosophila is a powerful system for modelling FTD/ALS. The goal of my proposal is to identify genes that can reverse or delay pathological changes in a specific Drosophila model of FTD/ALS. These flies exhibit features that closely resemble the clinical symptoms: impaired synaptic function, brain degeneration and shortened lifespan. I will: 1) Analyse several large gene deletions searching for the genes that ameliorate the impaired synaptic function in FTD/ALS flies; 2) Assess the ability of these newly identified genes to improve other FTD/ALS symptoms: reduced lifespan and brain degeneration. These genes can subsequently be tested in mammalian species as pharmacological targets for FTD/ALS and similar disorders.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL