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 3

TZ slows neurodegeneration, increases dopamine, and improves motor performance in 6-OHDA–treated rats.

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TZ slows neurodegeneration, increases dopamine, and improves motor perfo...
(A) Schematic for experiments in B–G. 6-OHDA (20 μg) was injected into the right striatum of rats on day 0. TZ (70 μg/kg) or saline was injected i.p. daily for 2 weeks, beginning 2, 3, 4, or 5 weeks after 6-OHDA injection. Assays were performed at 0 and 2–7 weeks. (B) Percentage of TUNEL-positive SNc cells. n = 6. (C) Quantification of TH protein levels assessed by immunoblotting in the striatum, normalized to control. n = 6. (D and E) Percentage of SNc cells positive for TH immunostaining (D) and intensity of TH immunostaining in striatum (E) 7 weeks after 6-OHDA injection. TZ treatment was administered from week 5 to week 7. n = 6. (F) Dopamine content in the right striatum relative to the left (control) striatum. n = 6. (G) Results of the cylinder test. 6-OHDA was injected into the right striatum, impairing use of the left paw. The assay was performed 7 weeks after 6-OHDA injection. TZ treatment was given from week 5 to week 7. n = 4 for control group and n = 10 for the two 6-OHDA groups. In C, D, E, and G, data points represent individual rats, and bars and whiskers indicate the mean ± SEM. Blue indicates controls and red indicates TZ treatment. Supplemental Table 3 shows statistical tests and P values for all comparisons. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test (B and F), Kruskal-Wallis with Dwass-Steele-Critchlow-Fligner test (C, D, and E), and Friedman with Dunn’s test (G).