Mitochondria must produce the chemical energy store molecule ATP in order for cells to function. The neurons lost in Parkinson’s disease are particularly vulnerable on this front, and the state of their mitochondrial function is important in determining how vulnerable a patient is to the underlying protein aggregation mechanisms that drive cell dysfunction and death. Researchers here discuss a protein that is rate-limiting in the production of ATP via glycolysis in neurons, and show that even slightly upregulating its expression can be protective. One might think that this is an enhancement that could be generally beneficial to brain cells and brain function, given a safe means of upregulation, as the brain is usually running at the very edge of metabolic capacity even in youth.
The brain is a metabolically vulnerable organ suffering acute functional decline when fuel delivery is compromised. We previously showed that central nervous system nerve terminals rely on efficient activity-dependent up-regulation of ATP synthesis to sustain function and undergo abrupt synaptic collapse when this process fails. Reduced fuel delivery to the brain is correlated with aging and is an early predictor of eventual neurological dysfunction, suggesting that as fuel delivery becomes compromised, synaptic function becomes increasingly vulnerable to genetic metabolic lesions. Parkinson’s disease (PD) has long-been thought to be, in part, driven by metabolic vulnerability of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) as two of the earliest identified genetic drivers of PD, PARK2 and PARK6, when mutated, compromise the integrity of mitochondria.
Several recent discoveries point to a critical but unexpected outsized role of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) in protecting neurons against neurological impairment. PGK1, the first ATP-producing enzyme in glycolysis, catalyzes the sixth step in this 10-step enzymatic cascade. A chemical screen of a subset of FDA-approved drugs capable of suppressing cell death identified terazosin (TZ) as a weak (~4%) off-target activator of PGK1. TZ was subsequently shown to confer significant protection in numerous models of PD (mouse, rat, Drosophila, and human induced pluripotent stem cells), implying that contrary to expectations, PGK1 activity is a critical modulator of glycolytic throughput. Clinical use of TZ for treatment of benign prostate hyperplasia provided data for a retrospective analysis, which showed that prolonged use of TZ reduced the risk of developing PD by up to ~37% compared to tamsulosin, whose chemical structure differs significantly from TZ but has the same molecular target.
These data all predict that PGK1 activity is a crucial leverage point in neuronal bioenergetic control and that bioenergetic deficits, in turn, underpin many forms of PD. Here, we demonstrate that PGK1 is the rate-limiting enzyme in axonal glycolysis and that modest changes in PGK1 activity accelerate neuronal ATP production kinetics capable of reversing the synaptic deficit driven by the PARK20 mutation. We identified PARK7/DJ-1, the PD-associated molecular chaperone, as a necessary gene for PGK1 to up-regulate ATP production as loss of PARK7/DJ-1 itself led to deficits in neuronal glycolysis that impaired the ability of PGK1 up-regulation to provide protection. We showed that increasing PGK1 abundance in vivo offered strong protection against striatal DA axon dysfunction. These data strongly support the idea that PGK1 serves as a critical lever arm in controlling axonal bioenergetics.
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