Dr Kinghorn’s research group seeks to understand the underlying pathogenic mechanisms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases, using the fruit fly Drosophila melanogaster, as well as cellular models of disease. In particular, our research is focused on unravelling the underlying mechanisms linking genes involved in endosomal-lysosomal intracellular trafficking pathways to Parkinson’s disease.
PROJECT 1: LYSOSOMAL STORAGE DISORDER GENES AND PARKINSON'S DISEASE
Lysosomal storage disorders (LSDs) are a group of metabolic disorders characterized by the accumulation of non-degraded storage material within the lysosome, the site of the breakdown of unwanted cellular waste. The lysosome is essential for a number of processes to occur within the cell, including phagocytosis, endocytosis and autophagy. Together these pathways are responsible for the trafficking and degradation of misfolded and aggregated proteins, such as α-synuclein, the main protein found in the brains of PD patients. Defects in this system are associated with Parkinson’s disease (PD) and neuronal cell loss. Consistent with this, there is increasing evidence implicating changes in LSD genes in PD. The precise mechanisms linking lysosomal dysfunction to cell death are unknown.
We are studying the commonest LSD gene linked to PD, known as GBA1, using fruit fly models. By studying the aberrant pathways in these models, we hope to gain further insights into how the loss of GBA1 gene activity and lysosomal abnormalities lead to PD.
PROJECT 2: FLY MODELS OF PLA2G6-ASSOCIATED NEURODEGENERATION
Mutations in the PLA2G6 gene at the PARK14 locus are the cause of a group of disorders referred to as PLA2G6-associated neurodegeneration (PLAN), comprising infantile neuroaxonal dystrophy and dystonia-parkinsonism. More recently PLA2G6 mutations have been linked to early onset Parkinson’s disease. PLA2G6 encodes an enzyme called phospholipase A2, which is responsible for the recycling of cell membrane phospholipids. Loss of normal enzyme function leads to membrane defects in the cell, including at the synapse and in mitochondria. Using fly models of PLA2G6 loss-of-function, we are interested in understanding how defects in this gene lead to neurodegeneration.