I continue reading up on why we see the particular phenotype of ALS (called MND in the UK) and Parkinsons.
The answer seems to be that those particular neurons not only have a high energy usage, but also have a high proportion of energy generated from OxPhos rather than glycolysis. This means that when they are short on melatonin they are hit harder than other cells.
Increasing PGK1 expression, and only PGK1 expression, allowed sugar-starved neurons to perform like their counterparts that had adequate access to fuel. Treating neurons with terazosin had a similar effect. These interventions did not affect the resting levels of ATP in neurons that had not yet been stimulated. Rather, the treatments allowed sugar-starved neurons to make ATP on time. Ryan’s team concluded that PGK1 is the rate-limiting step in glycolysis.
What I find weird is that neurons with the lowest reliance on glycolysis (dopaminergic) are hit first. I would assume the opposite!
In PD, not all neurons are vulnerable to disease, and this vulnerability has been associated with elevated levels of reactive oxygen species (ROS) and higher basal rates of mitochondrial oxidative phosphorylation, indicating that these neurons have higher energy requirements.
In a comprehensive study targeting PGK1 in preclinical PD models, MPTP-injected mice had increased levels of pyruvate and ATP in the striatum and substantia nigra following treatment with the PGK1 activator terazosin, corresponding with increased numbers of dopaminergic neurons
