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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

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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 5

TZ improves TH levels and motor performance in genetic models of PD.

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TZ improves TH levels and motor performance in genetic models of PD.
Dat...
Data points are from individual mice and groups of flies. (A–E) WT (w1118) and PINK15 flies received TZ or vehicle for 10 days beginning on the first day after eclosion. Day 10 assays included: (A) Example of wing posture defect and percentage of w1118 and PINK15 flies with wing posture defects. n = 6, with 80 flies for each treatment in each trial. (B and C) Example of TH Western blot (B) and quantification of TH (C). n = 5, with 40 fly heads for each treatment in each trial. (D) ATP content in brains (relative to w1118). n = 3, with 200 fly heads for each treatment in each trial. (E) Climbing behavior of flies. n = 3, with 100 flies for each treatment in each trial. (F) Climbing behavior of LRRKex1 male flies. n = 6, with 100 flies for each treatment in each trial. (G–K) TZ administration to mThy1-hSNCA–transgenic mice. (G) Schematic for experiments in panels H–K. (H) Example of Western blot of α-synuclein in striatum and SNc. (I and J) Quantification of α-synuclein in striatum and SNc. n = 5. (K) Duration that mice remained on an accelerating rotarod. n = 5. Data are from individual groups of flies (A–F) and individual mice (I–K). 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 1-way ANOVA with Tukey’s test (D) and Kruskal-Wallis with a Dwass-Steele-Critchlow-Fligner test (A–C, E, F, and I–K).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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