Molecular characterisation of mitochondrial disease, using Drosophila melanogaster as model system
Ragnar Söderberg Foundation
Parkinson's disease & PD-related disorders
Alpha-synuclein is known to contribute to the pathogenesis of Parkinson´s disease (PD) through the formation of toxic aggregates, oligomers, that lead to axonal and synaptic pathology and cell death. Degradation of these toxic intermediates is a promising method to reduce neuronal loss. In addition, there is evidence from autopsy studies that increased cellular levels of alfa-synuclein will cause down-regulation of factors involved in the regulation of dopamine neuron survival and function, most notably the transcription factor Nurr1, which regulates key genes for dopaminergic neurotransmission as well as the expression of the GDNF receptor, Ret. This study will be performed in the rat AAV-alfa-synuclein model, developed and established in the host laboratory, which replicates most of the pathophysiological features of PD. The project is based on two working hypotheses: (i) that impaired expression of the Ret receptor, induced by increased cellular levels of alfa-synuclein, will make the affected DA neurons non-responsive to GDNF and thus more vulnerable to the cellular stress induced by alfa-synuclein, and (ii) That the ability of DA neurons to resist to alfa-synuclein toxicity depends on the efficiency of the lysosome/autophagy pathway, and that pharmacological or genetic-based stimulation of its activity may provide a powerful approach to counteract alfa-synuclein induced damage.