The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson’s Models

Abstract

SUMMARY Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using datasets of established daf-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-assoicated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease. An outcome of this strategy was the identification of gpi-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor, DAF-16/FOXO, to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

“…Although the selective enrichment of quinone modified proteins in the aged SN region argues for a correlation between the quinone modification of proteins and the age-dependent selective vulnerability of SN dopaminergic neurons, the connection between quinone modification of the protein targets identified in our study and PD still remains to be proven. However, it is interesting to note that the relevance of glucose metabolism to the pathogenic change in PD is consistent with the recent finding that glucose-6-phosphate isomerase (GPI), a key enzyme in glycolysis, protects dopaminergic neurons against α-synuclein proteotoxicity (Knight et al, 2014). Moreover, ENO1 and LDHB are two of the three proteins that were selectively oxidized in transgenic mice expressing pathogenic A30P α-synuclein (Poon et al, 2005).…”

MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death

“…Interestingly, glycolysis also plays a neuroprotective role in ␣-synuclein-mediated toxicity. For example, blocking glycolysis with 2-DG aggravated ␣-synuclein-induced dopaminergic neuron loss in Caenorhabditis elegans (37), and knocking down the glycolytic enzyme, glucose phosphate isomerase (GPI), exacerbated ␣-synuclein neurotoxicity, whereas overexpression of glucose phosphate isomerase rescued dopaminergic neurons in C. elegans, Drosophila, and mice (37). These studies indicate that an intact glycolytic pathway is necessary for neuronal survival and that a dysfunctional glycolytic pathway may worsen the cellular bioenergetic deficit in PD.…”

Metabolic Dysfunction in Parkinson’s Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism

“…GAPDH has been shown to directly regulate α-synuclein aggregation and apoptotic neuronal cell death, which appears to be independent from its role in glycolysis. Glucose phosphate isomerase 1 (GPI-1) was recently demonstrated to exert a protective effect against proteotoxic stress induced by α-synuclein in dopaminergic neurons and this effect was shown to be linked to glycolysis (Figure 2.2) [168]. We have observed that the mechanism by which α-synuclein enhances metabolic dysfunction induced by environmental toxicants is linked to an impairment of glycolysis [14].…”