Mapping mitochondrial contact sites during neuronal ageing and neurodegeneration in Drosophila

Mitochondria establish interactions with numerous cellular compartments, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. These interactions are central to neuronal functioning. However, focus has mainly been placed on mechanisms regulating mitochondria-ER contact sites and their role in ageing and neurodegeneration. Despite playing an important role in cellular function, mitochondria-lysosome and mitochondria-peroxisome contact sites are poorly explored. Furthermore, very little is known about these interactions in the context of ageing and neurodegeneration. Additionally, the lab has discovered that reduced mitochondrial motility regulates neuronal homeostasis during ageing in Drosophila, however, the underlying mechanisms are not well understood. One possibility is that reduced mitochondrial transport may play a role in contact formations during ageing and neurodegeneration and therefore in overall neuronal functioning.

The questions I am addressing with my project are:
- Are mitochondria-lysosome, mitochondria-peroxisome, and mitochondria-ER contact sites perturbed during 'normal' ageing?
- Are mitochondria-lysosome, mitochondria-peroxisome, and mitochondria-ER contact sites perturbed in the context of neurodegenerative diseases (e.g., Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease)?
- If there are changes in contact sites, are they the result of age-related or disease-related changes in neuronal transport of mitochondria/ER/lysosomes/peroxisomes?

To answer these questions, I will be using genetically encoded split-GFP probes coupled with live imaging of intact neurons in nervous system of adult Drosophila to measure and analyse the neuronal contacts sites that form between mitochondria and lysosomes/peroxisomes/ER during ageing and in Drosophila models of Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.