LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson's disease.

Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson's disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.