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.

Proteostasis of α-Synuclein and Its Role in the Pathogenesis of Parkinson’s Disease

“…iPSC-derived dopaminergic neurons with LRRK2 G2019S mutation present with the accelerated accumulation of α-Synuclein. Treatment with terazosin, which can activate phosphoglycerate kinase 1 (PGK1) and subsequently increase cellular ATP level, reverses the elevation of α-Synuclein (Cai et al, 2019). Importantly, a lower frequency and slower progression of PD, and reduced disease-related complications are found in individuals taking the prescribed drug terazosin (Cai et al, 2019).…”

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

“…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.…”

“…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 disease‐modifying 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 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 have been linked with levodopa‐responsive parkinsonism and nigrostriatal denervation, thus providing an association between decreased glycolysis and PD in humans .…”

Dopamine Release Neuroenergetics in Mouse Striatal Slices

“…Upregulation of glycolysis is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis (Manzo et al, 2019). Likewise, recent research in clinical models has shown that enhancing glycolysis attenuates PD symptoms (Cai et al, 2019). Further study to examine the different expression levels of the metabolic genes and proteins may uncover the underlying mechanisms driving the different preferences of ATP-producing pathways in the dSTR and the NAcc shell.…”