Alternative Pathway for Methyl Supply through the Coupling of SHMT1 and PEMT to Maintain Astrocytic Homeostasis in Parkinson's Disease

In Parkinson's disease, SHMT1 downregulation disrupts its interaction with PEMT in astrocytes, reducing SAM levels. This leads to H3K4me1 hypomethylation and decreased Slc1a2/Glul expression, ultimately exacerbating neuroexcitotoxicity and dopaminergic neuron loss. This study reveals a novel SHMT1‐PEMT link connecting one‐carbon and membrane phospholipid metabolism in PD pathogenesis. Abstract Serine Hydroxymethyltransferase 1 (SHMT1) plays a pivotal role in one‐carbon metabolism, facilitating the production of SAM. In this study, dysregulation of one‐carbon metabolism is reported in both Parkinson's disease (PD) patients and animal models, characterized by significantly downregulated expression of SHMT1. Astrocyte‐specific conditional knockout of Shmt1 decreased SAM level, exacerbated motor dysfunction, and dopaminergic neuronal loss in a PD mouse model. While SAM is conventionally generated through the one‐carbon cycle, the data indicate that, despite significant alterations in SHMT1, SAM remains unaffected while labeled 13C‐Serine. Intriguingly, isotopic labeling experiments revealed a significant association between SHMT1 and the production of PDME, an intermediate metabolite of the phosphatidylethanolamine methylation pathway. Consequently, PEMT is discovered as interacting with SHMT1. It is demonstrated that disruption of the interaction between SHMT1 and PEMT leads to SAM depletion, causing H3K4me1 hypomethylation, which in turn reduces the expression of Slc1a2 and Glul. As a result, decoupling of SHMT1 and PEMT in astrocytes ultimately exacerbates neuroexcitotoxicity and dopaminergic neuron loss in PD. Thus, the study elucidates the novel metabolic connection between SHMT1 and PEMT that links the astrocytic one‐carbon cycle and membrane phospholipid metabolism in PD. In Parkinson's disease, SHMT1 downregulation disrupts its interaction with PEMT in astrocytes, reducing SAM levels. This leads to H3K4me1 hypomethylation and decreased Slc1a2/Glul expression, ultimately exacerbating neuroexcitotoxicity and dopaminergic neuron loss. This study reveals a novel SHMT1-PEMT link connecting one-carbon and membrane phospholipid metabolism in PD pathogenesis. Abstract Serine Hydroxymethyltransferase 1 (SHMT1) plays a pivotal role in one-carbon metabolism, facilitating the production of SAM. In this study, dysregulation of one-carbon metabolism is reported in both Parkinson's disease (PD) patients and animal models, characterized by significantly downregulated expression of SHMT1. Astrocyte-specific conditional knockout of Shmt1 decreased SAM level, exacerbated motor dysfunction, and dopaminergic neuronal loss in a PD mouse model. While SAM is conventionally generated through the one-carbon cycle, the data indicate that, despite significant alterations in SHMT1, SAM remains unaffected while labeled 13 C-Serine. Intriguingly, isotopic labeling experiments revealed a significant association between SHMT1 and the production of PDME, an intermediate metabolite of the phosphatidylethanolamine methylation pathway. Consequently, PEMT is discovered as interacting with SHMT1. It is demonstrated that disruption of the interaction between SHMT1 and PEMT leads to SAM depletion, causing H3K4me1 hypomethylation, which in turn reduces the expression of Slc1a2 and Glul. As a result, decoupling of SHMT1 and PEMT in astrocytes ultimately exacerbates neuroexcitotoxicity and dopaminergic neuron loss in PD. Thus, the study elucidates the novel metabolic connection between SHMT1 and PEMT that links the astrocytic one-carbon cycle and membrane phospholipid metabolism in PD. Advanced Science, EarlyView.