Objective: Understanding the role of NNMT in initiation and progression of Parkinson’s disease (PD).

Background: 10-15% of all PD cases are caused by genetic factors, whereas environmental influences might also be of major importance. Epidemiological studies have linked the exposure to industrial toxicants to developing PD. NNMT, a niacin-metabolizing enzyme, might be a key factor in PD since research has shown that NNMT expression is significantly increased in the brains of post-mortem PD patients. NNMT might be involved in causing PD by environmental toxins, similar to the pro-toxin MPTP, which after its conversion to the highly poisonous MPP+ causes PD symptoms. NNMT might also be involved in the “toxification” processes of harmless precursors as its metabolic product, 1-methylnicotinamide (MNA), has striking similarities to the structure of MPP+. Interestingly, MNA has been shown to exert both neurotoxic and neuroprotective effects. This could be explained by a hormetic dose-dependent adaptive response mechanism.

Methods: Transgenic Caenorhabditis elegans were generated that express NNMT in the dopaminergic neurons. GFP was expressed in the dopaminergic neurons of these strains to follow their degeneration in vivo by using fluorescence microscopy. We also analyzed dopamine-dependent behaviors like locomotion and sensing of food or chemicals. All analyses were done using animals at different ages to monitor age-dependent neurodegeneration. Environmental toxins were evaluated for their ability to induce PD-like symptoms in an NNMT-dependent manner, and a genetic screen was performed to evaluate the mechanism behind neuronal NNMT action.

Results: We found that enzymatic activity of NNMT in dopaminergic neurons increases degeneration and influences dopamine-dependent behaviors in C. elegans. Strikingly, it also has neuroprotective effects, as shown by increased resistance against environmental toxins, and increases lifespan of the worms. The genetic screen revealed genes involved in stress response and autophagy that influence these phenotypes.

Conclusions: Moderate neuronal NNMT acts most likely as a double-edged sword – by exerting slightly toxic effects it stimulates a transcriptional adaptive response that influences neuronal autophagy and stress defense mechanisms to finally reach a state in which the cell becomes more resistant against environmental influences that could promote PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuronal-nicotinamide-n-methyltransferase-nnmt-in-parkinsons-disease/