It’s always good when a new way to look at a basically untreatable disease comes along. We’ll know soon if looking at filamin A will be useful for Alzheimer’s disease. Here’s another: something we’ve known about for years (polyphosphate) may be important in Amyotrophic Lateral Sclerosis (ALS). I used riluzole for ALS, but never saw any benefit. It may have slowed the decline, but riluzole never stopped disease progression.
It is stated that 10% of ALS is familial, but I think this is an overstatement. Even so mutations in a variety of proteins(superoxide dismutase 1 (SOD1) TDP43, C9orf72) do cause ALS, and studying them has taught us a lot about ALS. There is plenty of work to do. In 2016 a mere 160 mutations in the 153 amino acids of SOD1 had been found, but we still don’t know how they cause ALS despite hundreds of papers on the subject. The proteins have allowed us to make mouse models of ALS, by putting in one or the other of mutated SOD1, TDP43, C9orf72 in motor neurons (or in whole animals)
Some real gumshoe work led to polyphosphate [ Neuron vol. 110 pp. 1603 – 1605 ’22 ]. Obviously in ALS, the motor neurons die, but recent work has shown that motor neurons are killed by neighboring astrocytes (containing any of the 3 the mutant proteins), when they are cultured together. Normal astrocytes don’t do this.
So a lot of hard work found that it was polyphosphate in the supernatant fluid that was the killer.
So what is polyphosphate? It’s been known for years, and is found in ALL cells — bacterial, plant, animal. It also produced abiotically in volcanic exudates and deep sea steam vents. No one knows what it does, so it has been called a molecular fossil. Again teleology should inform biologic research (but it doesn’t). Polyphosphate must be doing something useful or it wouldn’t be present in all living cells.
Chemically, polyphosphate is a chain of HUNDREDS to THOUSANDS of phosphate residues linked by high energy phosphoanhydride bonds.
Like this —
HO – PO2 – OH + HO -PO2 -OH –> HO – PO2 – 0 – PO2 – OH + H20
— the – O – in the middle is the phosphoanhydride bond
The authors treated motor neurons in culture with polyphosphate and found that it killed 40% of them. So what? Schmidt’s law of pharmacology, says that enough of anything will do anything, So they looked at the spinal cords of patients dying of ALS and found that polyphosphate levels were higher than in neurologically normal controls.
So it’s open season on polyphosphate. Finding out what it does in normal cells, finding out how it kills motor neurons, finding out if decreasing its levels will help ALS (it does in cultures of motor neurons but that’s a long way from a living patient). It’s an entirely new angle on an awful disease, with no useful treatment. There is simply an enormous amount of work to be done.
Watch this space.
Chemiotics II 