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 4

TZ enhances Pgk activity to attenuate rotenone-impaired motor performance.

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TZ enhances Pgk activity to attenuate rotenone-impaired motor performanc...
(A) Schematic for experiments in panels B–F. Flies received rotenone (125 or 250 μM in food) with TZ (1 μM) or vehicle for 7 or 14 days. (B) Relative ATP content in the brains of w1118 flies that received 250 μM rotenone with or without TZ for 14 days. n = 6, with 200 fly heads for each treatment in each trial. (C) Climbing behavior of flies after 250 μM rotenone with TZ (1 μM) or vehicle for 7 days. Data show the percentage of flies that climbed up a tube (see Methods). n = 3, with 200 flies tested for each treatment in each trial. (D) Knockdown of Pgk in offspring of actin-Gal4 crossed with UAS-Pgk RNAi flies. Offspring of actin-Gal4 crossed with y1 v1 P [CaryP] attP2 were used as a genetic background matched control. n = 3, with RNA collected from 30 fly heads for each sample. (E) Pgk was knocked down in TH neurons by crossing UAS-Pgk RNAi flies with flies carrying the TH neuron-specific promoter (TH-Gal4) to produce TH>Pgk RNAi flies. Rotenone (250 μM) and TZ were administered as indicated for 7 days. Climbing behavior was measured on day 7. n = 8, with 200 flies tested for each treatment in each trial. (F) Pgk (UAS-Pgk) overexpression was driven by a dopaminergic neuron promoter (TH-Gal4), a pan-neuronal promoter (Appl-Gal4), a pan-cell promoter (Actin-Gal4), and a muscle-specific promoter (Mhc-Gal4). Rotenone (250 μM) was administered for 7 days, and climbing behavior was measured on day 7. n = 3, with 200 flies tested for each treatment in each trial. Data points represent individual groups of flies, and bars and whiskers show 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 Kruskal-Wallis with a Dwass-Steele-Critchlow-Fligner test (B), 1-way ANOVA with Tukey’s test (C and E), paired t test (D), and unpaired t test (F).