Investigating mitochondrial and glycolytic phenotypes in Drosophila and patient derived models of C9orf72 Amyotrophic Lateral Sclerosis

Introduction: ALS is a neurodegenerative disorder characterised by progressive upper and lower motor neurone loss. A GGGGCC repeat expansion in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction and changes to glycolysis have been observed in C9orf72-ALS patients and models of the disease. Further understanding of these changes could help the development of new targeted therapies for patients carrying this mutation. This thesis investigates how metabolism is altered in neurones derived from C9orf72-ALS patients and Drosophila models of C9orf72-ALS.

Results: Neurones from C9orf72-ALS patients displayed reduced mitochondrial membrane potential, increased mitoROS production and increased levels mtDNA. Mitophagy was impaired in C9orf72-ALS iNeurones, which appears to be due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. In Drosophila models of C9orf72-ALS, glucose uptake by neurones is increased, however feeding a high sugar diet could rescue locomotor deficits but not increase survival.

Discussion: These data show that mitochondrial function is impaired in C9orf72-ALS neurones. This thesis is one of the first to report a mitophagy deficit in C9orf72-ALS neurones, with in-depth characterisation showing a deficit in autophagosome production is likely responsible. These data also demonstrate that despite increases in glycolysis in Drosophila models of C9orf72-ALS, high sugar diets cannot rescue phenotypes. This thesis highlights the importance of further study into glycolysis and mitophagy in C9orf72-ALS as potential therapeutic targets for the disease.