[
International Worm Meeting,
2017]
The enzyme nicotinamide N-methyl-transferase (NNMT) is an essential contributor in various important epigenetic, reproductive, and metabolic processes. It plays a role in healthy aging, cellular stress response and resistance, and it regulates weight gain and the prevalence of obesity, among others. Although it is expressed and functionally active in the brain, its role in neurons remains obscure. This is surprising given that in vitro studies have shown NNMT to be a potential risk factor for psychiatric diseases like schizophrenia and neurodegeneration, especially in dopaminergic neurodegeneration typical of Parkinson's disease. Neurodegeneration is a pervasive major risk for increased mortality in the elderly. Here, we studied the role of neuronal NNMT in vivo using C. elegans. The nematodal ortholog of human NNMT is ANMT-1. In contrast to most in vitro studies, we found neuronal ANMT-1/NNMT overexpression to be neuroprotective in wild type and various disease models as the animals age. ANMT-1/NNMT uses methyl groups from S-adenosyl-methionine (SAMe). As the most important methyl group donor in the cell, SAMe also provides methyl groups for the methyltransferase B0285.4, the C. elegans ortholog of the human leucine carboxyl methyltransferase 1 (LGMT1). ANMT-1/NNMT titrates methyl groups from B0285.4/LGMT1, reducing its catalytic capacities. B0285.4/LGMT1 targets NPRL-2 (human NPR2-like, GATOR1 complex subunit), a known regulator of autophagy and cell growth. Autophagy is activated by neuronal overexpression of ANMT-1/NNMT, which acts by "clearing up" misfolded, dysfunctional and aggregated proteins within the neurons, maintaining proteostasis and healthy neuronal function in age. Furthermore, neuronal expression of ANMT-1/NNMT mediates increased neurotransmitter release, which may act as an endocrine-like signal in the whole animal to control metabolism, behavior, and extend lifespan. This study shows for the first time that ANMT-1/NNMT may contribute to neuronal health in vivo based on its direct or indirect regulation of cellular processes such as the induction of autophagy and endocrine-like signalling, which are critical for neuronal homeostasis, ultimately curtailing neurodegeneration, all the while promoting healthy aging.