Role of Nicotinamide N-methyltransferase in Genetic Models of Parkinsonís Disease
Rapid Response Innovation Awards, 2014
There is mounting evidence linking the metabolism of the vitamin niacin to Parkinsonís disease (PD). The enzyme nicotinamide N-methyltransferase (NNMT), a key enzyme of the niacin metabolism, might be a key factor in the development and progression of the disease. 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 ďtoxificationĒ process, which means that it transforms per se harmless compounds to neurotoxins that cause neurodegeneration, leading to PD.
We will investigate whether a high level 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 be unethical and unfeasible, we use a model organism, the tiny roundworm Caenorhabditis elegans. Model organisms are species that are investigated instead of humans to understand biological processes, assuming that findings in these organisms are at least in parts negotiable to other species. As it is easily possible to modify the genome of C. elegans, we aim to generate transgenic models that have genetic mutations, which in humans would lead to an enhanced PD risk. Together with these known mutations, we want to investigate what happens if we express the NNMT enzyme in C. elegansí neurons, and expose them to various environmental toxins, like herbicides.
Impact on Diagnosis/Treatment of Parkinsonís Disease:
In case we find a relationship between NNMT in neurons, other mutations, and toxin exposure, this would be an important new point in understanding and avoiding PD.
Next Steps for Development:
Further research could clarify if there are ways to inhibit the NNMT enzyme. At least, the substances that act as neurotoxins could be avoided or even banned from usage in agriculture, helping to create a healthier environment for everyone.
There is mounting evidence linking the vitamin niacin and enzyme nicotinamide N-methyltransferase (NNMT), the regulator of niacin metabolism, to Parkinson's disease (PD). In the brains of people with PD, NNMT is present in very high quantities. We aimed to investigate whether such high level of NNMT in the brain indeed can trigger or speed Parkinson's.
In this study, we modified the genes of Caenorhabditis elegans -- our model organism -- to create excess of NNMT in its dopamine-producing brain cells. By doing so, we created a model of PD with unusually high levels of this enzyme in the brain. We found that NNMT makes certain compounds in the environment toxic and, hence, represents an important risk factor for the loss of brain cells in PD. However, NNMT is also protective against most potential toxins, giving it the ability to save dopamine-producing brain cells from death. The same holds true when NNMT production in brain cells is accompanied by genetic changes -- mutations -- that increase the risk of PD. To summarize, NNMT exacerbates brain cell death in some cases and prevents it in other cases. We now know why the effect of NNMT varies, and can use this knowledge to predict the effect of NNMT in each particular case. In either scenario, NNMT is an important modulator of other risk factors, such as mutations or environmental influences, capable of protecting the brain as well as speeding the onset or progression of Parkinson's disease.
Presentations & Publications
Publication is planned for summer 2016, which will go along with conference presentations.
Assistant Professor at University of Montrťal, CHUM Research Center
Location: Montrťal, Quebec, Canada
Postdoctoral Researcher at University of Montrťal, CHUM Research Center
Location: Montrťal, Quebec, Canada