Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases
Rong Cai, … , Michael J. Welsh, Lei Liu
Rong Cai, … , Michael J. Welsh, Lei Liu
Published September 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4539-4549. https://doi.org/10.1172/JCI129987.
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Research Article Neuroscience

Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

Authors

Rong Cai, Yu Zhang, Jacob E. Simmering, Jordan L. Schultz, Yuhong Li, Irene Fernandez-Carasa, Antonella Consiglio, Angel Raya, Philip M. Polgreen, Nandakumar S. Narayanan, Yanpeng Yuan, Zhiguo Chen, Wenting Su, Yanping Han, Chunyue Zhao, Lifang Gao, Xunming Ji, Michael J. Welsh, Lei Liu

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Figure 1

TZ enhances glycolysis in the mouse brain.

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TZ enhances glycolysis in the mouse brain. Data points represent individ...
Data points represent individual mice. Blue indicates controls and red indicates TZ treatment. (A) Schematic of ATP production by glycolysis and oxidative phosphorylation. (B) Schematic time course for experiments in C–G. Eight-week-old C57bl/6 mice were given MPTP (20 mg/kg i.p.) or vehicle 4 times at 2-hour intervals. Then, TZ (10 μg/kg) or vehicle was injected i.p. once a day for 1 week. Assays were performed on day 7. (C–E) Pyruvate levels (C), citrate synthase (CS) activity (D), and ATP levels (E) were measured in mouse striatum. TZ doses are indicated in E. n = 6. Statistical comparison was made versus no TZ treatment. (F and G) Pyruvate (F) and ATP (G) levels in the mouse striatal region. Supplemental Table 3 shows statistical tests and P values for all comparisons. Bars and whiskers indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test (C and D), Kruskal-Wallis with Dunn’s test (E), and Kruskal-Wallis with Dwass-Steele-Critchlow-Fligner test (F and G).