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 6

TZ increases ATP content and decreases α-synuclein accumulation in iPSC-derived dopamine neurons from patients with PD.

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TZ increases ATP content and decreases α-synuclein accumulation in iPSC-...
(A) iPSC-derived dopamine neurons from 2 patients with PD (subjects 12 and 13) carrying LRRK2G2019S mutations and a healthy control (subject 11). Thirty-day-old dopamine neurons were plated and were treated with TZ (10 μM) 1 or 3 days later. The neurons were studied 24 hours after addition of TZ. We observed no difference between the 2 start dates and therefore combined the data. Representative immunofluorescence images of α-synuclein (SNCA, green), TH (red), and DAPI (nuclei, blue). (B) Percentage of TH-positive neurons with cytoplasmic accumulation of α-synuclein. n = 12. (C) ATP content in control and LRRK2G2019S iPSC–derived dopamine neurons. n = 12. 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.