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Cai R, Zhang Y, Simmering JE, Schultz JL, Li Y, Fernandez-Carasa I, Consiglio A, Raya A, Polgreen PM, Narayanan NS, Yuan Y, Chen Z, Su W, Han Y, Zhao C, Gao L, Ji X, Welsh MJ, Liu L. Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases. J Clin Invest. 2019 Oct 1;129(10):4539-4549. PubMed.
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University of York
The main claim of this paper is that a drug used to treat prostate overgrowth, terazosin (TZ), may benefit people with Parkinson’s. In particular it may reduce the risk of Parkinson’s, and/or slow its progression. Such a “disease-modifying therapy” would be very valuable, since most of the currently approved drugs reduce the symptoms, but do not slow the course of Parkinson’s. Since TZ is already approved for human use, it could be quickly repurposed for people with Parkinson’s. This drug would not be without risk, as it also reduces blood pressure, which may already be low in people with Parkinson’s, so careful evaluation of its safety is needed.
TZ is usually defined as an α1-adrenergic receptor antagonist—this means it acts on the cell surface, interacting with specific receptors for adrenaline, the flight-or-fight hormone. This effect of TZ is to relax blood vessels—but Cai et al. propose a second mechanism. They propose that TZ also acts on an enzyme inside the cell called phosphoglycerate kinase 1 (PGK1). The proposed interaction between TZ and PGK1 would increase the synthesis of ATP, the main source of energy in the cells. Lack of ATP production is a common feature of Parkinson’s, Alzheimer’s, and other neurodegenerative conditions.
The main strength of this paper is that it shows that TZ alleviates the progression of Parkinson’s-like effects in a range of living animal models—both genetic and environmental. TZ improves motor performance in each model, mediated (at least in part) by the dopaminergic neurons. Indeed, in the fly model, the availability of a very specific genetic manipulation shows convincingly that the TZ—PGK1 interaction is dopaminergic.
Additionally, the paper finds—from medical databases—that people taking TZ (or related compounds) had a lower risk of Parkinson’s than the general population.
The main weakness of the paper is that the mechanism of TZ—PGK1 interaction is not fully explored. How does the TZ get into the cell and bind to PGK1? Does it directly affect ATP production? There is little attempt to show that the effects are not due to the well-characterised adrenergic mechanisms, perhaps because these experiments are technically difficult. However, the fact that TZ benefits fly models of Parkinson’s as well as rodent models supports the idea that TZ is not acting by an adrenergic receptor mechanism, since flies have no adrenaline.
All of this is very encouraging, and indicates that TZ is a strong candidate for clinical trials to see if it can be repurposed for Parkinson’s. In this TZ joins other drugs (including UDCA and Exenatide) that affect energy metabolism. Additionally, other adrenergic drugs have been thought to be beneficial to people with Parkinson’s, e.g. salbutamol (Mittal et al., 2017), though their proposed mechanism did not involve PGK1.
References:
Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science. 2017 Sep 1;357(6354):891-898. PubMed.
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