Identification of novel modifiers of synaptic function, neurodegeneration and longevity in a Drosophila FTD/ALS model

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.