The potential role of glucose metabolism, lipid metabolism, and amino acid metabolism in the treatment of Parkinson's disease

Abstract

Purpose of review: Parkinson's disease (PD) is a common neurodegenerative disease, which can cause progressive deterioration of motor function causing muscle stiffness, tremor, and bradykinesia. In this review, we hope to describe approaches that can improve the life of PD patients through modifications of energy metabolism.

Recent findings: The main pathological features of PD are the progressive loss of nigrostriatal dopaminergic neurons and the production of Lewy bodies. Abnormal aggregation of α-synuclein (α-Syn) leading to the formation of Lewy bodies is closely associated with neuronal dysfunction and degeneration. The main causes of PD are said to be mitochondrial damage, oxidative stress, inflammation, and abnormal protein aggregation. Presence of abnormal energy metabolism is another cause of PD. Many studies have found significant differences between neurodegenerative diseases and metabolic decompensation, which has become a biological hallmark of neurodegenerative diseases.

Summary: In this review, we highlight the relationship between abnormal energy metabolism (Glucose metabolism, lipid metabolism, and amino acid metabolism) and PD. Improvement of key molecules in glucose metabolism, fat metabolism, and amino acid metabolism (e.g., glucose-6-phosphate dehydrogenase, triglycerides, and levodopa) might be potentially beneficial in PD. Some of these metabolic indicators may serve well during the diagnosis of PD. In addition, modulation of these metabolic pathways may be a potential target for the treatment and prevention of PD.

Keywords: Parkinson's disease; amino acid metabolism; glucose metabolism; lipid metabolism.

FIGURE 1

Overview of the glucose metabolism and fatty acids metabolism in neuronal and astrocytic compartments. Neurons and astrocytes can take up glucose respectively through GLUT3 and GLUT1. Glucose is phosphorylated by HK to generate G6P, which is subsequently routed in glycolysis and PPP. The end product of glycolysis is pyruvate. Acetyl‐CoA, derived from pyruvate or fatty acid oxidation, is channeled into the TCA cycle coupled with OXPHOS and ATP synthesis. Impaired mitochondrial energy metabolism leads to ROS accumulation which results in cell death. ATP generation is dependent on OXPHOS, while glucose metabolism is mainly directed toward the PPP to generate NADPH. NADPH is crucial for the GSH, which can reduce the accumulation of ROS. GSH can be shuttled to neurons to maintain redox homeostasis. LA enters the neuron by ANLS, and it can be converted to pyruvate by LDH, which provide energy for neurons. ANLS, astrocyte‐neuron‐lactate shuttle; G6P, glucose‐6‐phosphate; G6PD, glucose‐6‐phosphate dehydrogenase; GLUT1, glucose transporter 1; GLUT3, glucose transporter 3; GSH, glutathione; HK, hexokinase; LA, lactic acid; LDH, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PPP, pentose phosphate pathway; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.

FIGURE 2

Overview of the lipid metabolism dysregulations in PD brain. Loss of PLA2 gene function results in lipid peroxidation and impaired mitochondrial function, which is associated with ferroptosis. 24‐OHC can activate tyrosine hydroxylase and promote dopamine synthesis. 27‐OHC can increase the level of α‐Syn, which induces apoptosis and eventually leads to neuronal death. The formation of lipid droplets can decrease the levels of ROS, which can inhibit apoptosis. Excess PUFA can increase the levels of α‐syn and ROS, which leads to apoptosis. PUFA forms TAG, which can be stored in lipid droplets. Inhibition of TAG formation makes neurons more vulnerable to α‐Syn toxicity. Disruption of cholesterol metabolism causes lysosomal dysfunction, which leads to autophagy dysfunction. PD, Parkinson's disease; PLA2, phospholipase A2; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; TAG, triacylglycerol; α‐Syn: α‐synuclein.