Enhancement of glycolysis: A Potential Disease‐Modifying Strategy for Parkinson's Disease

Disease-modifying therapy is a major unmet need in Parkinson’s disease (PD). In a recent article, Cai and colleagues provide evidence that terazosin has diseasemodifying effects in toxic and genetic animal models of PD, likely mediated through enhancement of glycolysis. Terazosin (TZ) is an α1-adrenergic receptor antagonist licensed for the treatment of prostatism that has been shown to increase cell phosphoglycerate kinase (PGK1) activity. The glycolytic pathway is composed of 10 different enzymatic reactions, and PGK1 is the first that directly leads to the generation of adenosine triphosphate (ATP). In a series of experiments, they first administered TZ to normal mice and observed an increase of ATP levels in the substantia nigra pars compacta (SNc), striatum, and cortex. Subsequently, they demonstrated that the administration of TZ ameliorated SNc and striatum neuronal loss and improved motor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. Similarly, neuronal loss was attenuated in the striatum, and motor performance was improved after TZ treatment in the 6-hydroxydopamine mouse model. This effect was seen both when TZ was administered at the same time as the neurotoxin and after a delay of 1 week, suggesting it might modify neuronal loss after toxin exposure. As an additional model, they treated Drosophila melanogaster with rotenone, a mitochondrial complex I inhibitor. Rotenone treatment decreased ATP brain levels andDrosophila-climbing behavior. These effects were partially ameliorated by the administration of TZ, a protective effect that was abolished by knocking down Drosophila Pgk. Conversely, PGK1 overexpression in Drosophila tyrosine hydroxylase neurons made flies resistant to rotetone-induced behavioural effects. The authors also explored genetic models and demonstrated that TZ partially improved ATP and tyrosine hydroxylase levels and motor deficits in Drosophila mutant PTEN-induced kinase 1 (PINK1) and Leucine-rich repeat kinase (LRRK) models. Furthermore, TZ partially prevented α-synuclein accumulation in the SNpc and striatum in a wild type (WT) human α-synuclein mousemodel and in dopaminergic neurons with the LRRK2 mutation. Lastly, the authors researched the Parkinson’s Progression Markers Initiative database and found that PD patients (n = 7) who used TZ had slower disease progression and motor complications when compared with the other 269 patients who were not taking TZ. Also, in an independent database, 2879 patients who used TZ or related PGK1-enhancing α1-adrenergic antagonists had a reduced likelihood of having a PD diagnosis when compared with 15,409 patients using tamsulosin (α1-adrenergic antagonist without PGK1 enhancement effects). The study by Cai and colleagues provides evidence that TZ has potential disease-modifying effects in several PD models through the enhancement of glycolysis. X-linked recessive mutations in PGK1 cause enzymatic deficiency through haploinsufficiency and havebeen linkedwith levodopa-responsive parkinsonism and nigrostriatal denervation, thus providing an association between decreased glycolysis and PD in humans. Moreover, PGK1 is in the Xq21-q25 location of the PARK12 susceptibility locus as reported in three different PD-linkage studies. The limitations of the study by Cai and colleagues are inherent to the shortcomings of animal models to recapitulate human PD pathology and the retrospective analysis of datasets with small number of patients treated with TZ. However, this study opens new directions for potential disease-modifying therapy in PD by targeting the glycolytic pathway.