Molecular insight into Parkinson’s disease
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s, display a progressive loss of nerve cells in specific areas of the brain. Despite extensive research on the underlying aetiology, insight into the implicated molecular mechanisms of cell loss is lacking. Scientists of the EU-funded RECYCLING PARKINSON project wished to identify genes directly or indirectly implicated in the pathogenesis of Parkinson’s disease. For this purpose, they performed a forward genetic screen in the fruit fly Drosophila melanogaster, which is a very good model for studying orthologous genes. Scientific activities focused on the hypothesis that synaptic dysfunction, and in particular, recycling of neurotransmitter-filled vesicles could be responsible for disease pathology. They isolated over 85 mutants of non-canonical vesicle recycling that helped them investigate synaptic pathogenesis of these diseases. Researchers made interesting observations in flies’ having a mutant in the Parkinson’s related gene Pink1. They discovered that removing the mitochondrial protein nitric oxide associated 1 (NOA1) has a beneficial influence on motor skills in these flies. This suggested a potential interaction between Pink1 and NOA1, given that they localise in mitochondria and may function in the same pathway. In another part of the project, scientists overexpressed alpha-synuclein in the nervous system of Drosophila, a protein found in Lewy bodies in the brains of Parkinson’s patients. They discovered that these flies have defective motor skills leading to reduced climbing performance. Further screening identified 19 mutations that restored this climbing defect. The isolated genes encoded mitochondrial proteins, as well as proteins involved in microtubule dynamics and in ubiquitination. Overall, the findings of the RECYCLING PARKINSON project provided fruitful insight into the molecular mechanisms underlying synapse dysfunction and neuronal cell loss in Parkinson’s disease. Considering that the treatment options for the majority of neurodegenerative diseases are nil or only palliative in nature, these results lay the foundation for the identification of new therapeutic targets.
Keywords
Parkinson’s disease, RECYCLING PARKINSON, synaptic dysfunction, Pink1, NOA1
