In vivo and in situ modelling of endoplasmic reticulum shaping defects on mitochondrial function in hereditary spastic paraplegias (360G-Wellcome-200927_Z_16_A)

Overall this project aims to study the mechanisms underpinning neurodegeneration caused by mutations in ER-shaping proteins. Key goals: • Generate patient-variant Drosophila models of HSP. • Determine how loss of ER- shaping proteins disrupts mitochondrial organisation in motor neurons in vivo. • Identify how findings from Drosophila translate to human models of HSP. • Elucidate the function of the ER and mitochondria in long motor neurons and identify the important role that disruption of these organelles plays in neurodegeneration. • Further our understanding of the cellular events contributing to neurodegeneration in HSP which may lead to the identification of novel targets to treat this disorder. • Develop expertise in state-of-the- art technologies including CRISPR/Cas9 genome modification and high-resolution live imaging techniques. • Advance my research career by building collaborative links with international experts in the field of neurodegeneration. These include Joseph Gleeson from UC-San Diego, a clinician with access to one of very few Ari61P1 patients as well as Mark Terasaki, Jennifer Lippincott-Schwartz and Eric Betzig who are world-renowned experts in the study of endoplasmic reticulum and novel imaging technologies. • Mature as a research scientist by conducting my research working together with principle investigators and highly experienced lab members.