Nicotinamide-N-methyltransferase controls behavior, neurodegeneration and lifespan by regulating neuronal autophagy

Abstract

Nicotinamide N-methyl-transferase (NNMT) is an essential contributor to various metabolic and epigenetic processes, including the regulating of aging, cellular stress response, and body weight gain. Epidemiological studies show that NNMT is a risk factor for psychiatric diseases like schizophrenia and neurodegeneration, especially Parkinson’s disease (PD), but its neuronal mechanisms of action remain obscure. Here, we describe the role of neuronal NNMT using C. elegans. We discovered that ANMT-1, the nematode NNMT ortholog, competes with the methyltransferase LCMT-1 for methyl groups from S—adenosyl methionine. Thereby, it regulates the catalytic capacities of LCMT-1, targeting NPRL-2, a regulator of autophagy. Autophagy is a core cellular, catabolic process for degrading cytoplasmic material, but very little is known about the regulation of autophagy during aging. We report an important role for NNMT in regulation of autophagy during aging, where high neuronal ANMT-1 activity induces autophagy via NPRL-2, which maintains neuronal function in old wild type animals and various disease models, also affecting longevity. In younger animals, however, ANMT-1 activity disturbs neuronal homeostasis and dopamine signaling, causing abnormal behavior. In summary, we provide fundamental insights into neuronal NNMT/ANMT-1 as pivotal regulator of behavior, neurodegeneration, and lifespan by controlling neuronal autophagy, potentially influencing PD and schizophrenia risk in humans.

PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

“…The NNMT pathway has been linked to lifespan and aging [66][67][68][69], to sirtuin protein stabilization in positive a feedback loop to the pathway in Fig. 6b involved in energy regulation and obesity [52,70,71] and to epigenetics in cancer and stem cell status [52,[72][73][74] (reviewed by [75]).…”

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

“…The NNMT pathway has been linked to lifespan and aging (Calvani et al, 2014;Neelakantan et al, 2019;Schmeisser et al, 2013;Schmeisser and Parker, 2018), to sirtuin protein stabilization in positive a feedback loop to the pathway in Figure 6C involved in energy regulation and obesity (Hong et al, 2015;Kraus et al, 2014;Strom et al, 2018), and to epigenetics in cancer and stem cell status (Jung et al, 2017;Sperber et al, 2015;Ulanovskaya et al, 2013;Xie et al, 2014) (reviewed by (Pissios, 2017)). We show that PGRMC1 Y180 modulates this system.…”

Genetic and functional diversification of chemosensory pathway receptors in mosquito-borne filarial nematodes

“…Given conservation of NAM-receptor interactions across these phyla, we expect Brugia OSM-9 orthologs to also respond to NAM. However, the pharmacology and subunit interactions of Brugia OSM-9 may differ (e.g., filarial parasites do not have a homolog of ocr-4 ( Figure 3A)), and NAM is an endogenous metabolite in C. elegans that has pleiotropic effects (54,(56)(57)(58)(59)(60) . This compelled us to use a genetic approach to more directly test whether Brugia OSM-9 and TAX-4 are involved in parasite chemotaxis behavior.…”