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

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.

烟酰胺N-甲基转移酶（Nicotinamide N-methyl-transferase, NNMT）是多种代谢与表观遗传过程的关键调控因子，参与调控衰老、细胞应激反应及体重增加等过程。流行病学研究显示，NNMT是精神分裂症等精神疾病及神经退行性病变（尤其是帕金森病（Parkinson’s disease, PD））的风险因子，但其神经元层面的作用机制仍不明晰。本研究以秀丽隐杆线虫（C. elegans）为模型，阐释神经元NNMT的生物学功能。我们发现，线虫的NNMT同源物ANMT-1可与甲基转移酶LCMT-1竞争S-腺苷甲硫氨酸（S-adenosyl methionine）提供的甲基基团，进而调控LCMT-1的催化活性，其作用靶标为自噬调节因子NPRL-2。自噬是降解细胞质物质的核心细胞分解代谢过程，但目前对衰老过程中自噬的调控机制知之甚少。本研究揭示了NNMT在衰老过程中调控自噬的重要作用：神经元ANMT-1高活性可通过NPRL-2诱导自噬，该过程可维持老年野生型动物及多种疾病模型的神经元功能，同时影响机体寿命。然而在年轻动物体内，ANMT-1活性会扰乱神经元稳态与多巴胺能信号传导，引发行为异常。综上，本研究阐明了神经元NNMT/ANMT-1通过调控神经元自噬，作为行为、神经退行性病变与寿命关键调控因子的核心机制，或可影响人类帕金森病与精神分裂症的发病风险。