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Synaptic vesicle recycling and Parkinson’s disease

Final Report Summary - RECYCLING PARKINSON (Synaptic vesicle recycling and Parkinson’s disease)

Neurodegenerative diseases have a devastating impact on the lives of patients, their family and friends and broader on the society as a whole. For many of these diseases no or only palliative treatment exists. Alternatively, medication exists but has drawbacks in the form of side effects or reduced effectiveness in time. Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s display a progressive loss of nerve cells in specific areas of the brain. The understanding of the molecular mechanisms underlying this loss of cells is still far from complete.
My project entitled “Recycling Parkinsons” intended to find genes that are directly or indirectly involved in the pathogenesis on Parkinson’s disease. For that purpose I performed a genetic screen in
the fruit fly Drosophila melanogaster. Drosophila has orthologous genes for many of the genes that
are found to be mutated in the familial forms of Parkinson’s. One of these genes is Pink1 and I found
that removing the mitochondrial protein Nitric Oxide Associated 1 (NOA1) has a beneficial influence on motor skills in flies lacking Pink1. Because the function of NOA1 has not been fully elucidated, I studied its role in mitochondria of the nerve endings that signal to the muscles of Drosophila larvae. I found that animals lacking the gene, or having specific point mutations leading to alterations of the catalytic GTPase domain in NOA1had defects in their electrophysiological response (ERG) to light. I could however not completely rule out that this phenotype was not due to genetic alterations is other genes, since reintroduction of the Drosophila gene for NOA1, only partially rescued the ERG defect. Since we did not find robust other phenotypes I decided to discontinue aim1 and focus on the results of aim 2 and 3.
A second aim of the study was to find out how reduction of NOA1 can have a beneficial influence on motor defects seen in Pink1 mutants. The promising results initially obtained, showed alleviated defects of fying behavior in pink1;Dmnoa1 double mutants could not be found in many other assays tested. For instance mitochondrial morphology, which is disturbed in pink1 mutants, was even more profoundly affected in double mutants, contradicting the evidence on the behavioral level. I therefore could not work out the mechanism by which NOA1 interacted with Pink1. The experiments for aim 2 were thus also discontinued.
The most exciting progress is made in a screen for genes that interact with alpha-synuclein, a protein found in Lewy bodies in the postmortem brains of Parkinson’s patients. I over expressed alpha-synuclein in the nervous system of Drosophila and found that flies have defective motor skills leading to reduced climbing performance. In this way I tested 86 mutants and found 19 mutations that restore climbing in flies expressing aberrant levels of alpha-synuclein. All 19 mutations were sequenced using next generation sequencing and the mutations are now being verified. So far I found mutations in mitochondrial genes, but also genes encoding for proteins involved in microtubule dynamics and in ubiquitination. In collaboration with researchers from the Leiden University Medical Center (LUMC), the host institute, I have performed research on the genes affected in Duchenne muscular dystrophy. In these projects I contributed as a geneticist and with my electrophysiological expertise. I have helped train the next generation of scientists by lecturing at the Bachelor, Master and PhD level. All these accomplishments have advanced me as a scholar.