Grant: CIHR Fellowship

There is mounting evidence linking the enzyme nicotinamide N-methyltransferase (NNMT), a key enzyme of the niacin metabolism, to the development and progression of Parkinson's disease (PD). This idea arises from data showing that NNMT expression is significantly higher in the brain of patients who have died of PD. NNMT could be responsible for a so-called "toxification" process, which means it metabolizes per se harmless compounds to neurotoxins that cause neurodegeneration. We hypothesize that this could, alone or in combination with other genetic predispositions, lead to PD. To assess this hypothesis, we will investigate whether high levels of neuronal NNMT, accompanied by exposure to toxins and/or other mutations that increase the risk for neurodegeneration, indeed has an influence on initiation or progression of PD. Since studying this in humans would barely be feasible we use model organisms, the roundworm Caenorhabditis elegans and the zebrafish Danio rerio. We will generate transgenic worms that have NNMT expressed in their dopaminergic neurons and analyze if these worms show loss of function and degeneration of these neurons during the aging process. We will expose these worms to a number of environmental toxins to investigate if this amplifies neurodegeneration. Furthermore, we want to cross these strains into other models of genetic mutations that are known to be causative for PD and investigate 1.) whether this would amplify the progression of PD symptoms in the worm models, and 2.) to identify the molecular mechanisms that lead to these symptoms. Subsequently, we aim to perform some key experiments in zebrafish to investigate if our findings are applicable to vertebrate organisms. Proving the role of NNMT in PD would reveal a new important risk factor and a starting point in the development of new therapeutic approaches in the management of PD.