Could calcium be the key?

A powerful way to find causes and cures for diseases that occur in its common, non-familial pattern (which we call “sporadic”) is to find and study the genetic mutation(s) causing the same disease to occur in a rare, familial pattern.  The protein(s) encoded by those genes can then be investigated for a non-genetically-determined role in the sporadic form of the disease.

I know this from my own experience studying Parkinson’s disease.  In 1990, I found and worked up a large Italian-American family that, long story short, proved to have 61 members with PD over 5   generations.  My colleagues and I found the mutation, which was in the gene encoding alpha-synuclein, a protein not previously suspected of a relationship to PD.  That protein then proved to have a central role in sporadic PD even though virtually no one with that form of the disease has a mutation in that gene.  Now, treatments and diagnostics aimed at that protein are being tested.

That’s one reason I was excited to see a paper published this week by researchers mostly at Washington University in St. Louis, with contributions from UCSF, the University of Sao Paulo, Brazil, and the Neural Stem Cell Institute in Rensselaer, NY.  The first author was Miguel Minaya, PhD, a molecular geneticist working at WUStL in the lab of Celeste Karch, PhD, with whom I’ve collaborated in the past.  Her lab is a world leader in using stem cells to model neurodegenerative diseases.

There are 50 mutations in the MAPT gene (which encodes tau protein) that produce a hereditary disease that looks a lot like PSP at all levels and is called “frontotemporal lobar degeneration with mutations in the tau gene” or FTLD-tau.  The researchers divided those mutations into 3 logical groups based on their mechanism of action and chose one mutation from each group to test.  To do that, they used stem cells derived from skin biopsies of people with one of the three chosen mutations.  They measured those cells’ “expression” of all the other genes.  (Gene “expression” means how active a gene is in actually encoding its protein, as measured by levels of its specific messenger RNA.)  They created control group of stem cells by using the gene editing tool CRISPR to correct the PSP-causing mutation.  That way, the disease cells and the controls were genetically identical except for that one mutation.

They found that the expression of 275 of the 20,000 human genes differed in the uncorrected stem cells compared to the corrected stem cells.  What many of those 275 had in common, they discovered, was that they helped control calcium levels inside the cells.

The experimenters next did the obvious and looked at calcium levels in the two sets of stem cells, finding lower levels in the uncorrected group.  That showed that these genes known to affect calcium were actually doing so, as opposed to only theoretically doing so.  They obtained additional confirmatory evidence by imaging calcium in the cells and analyzing gene expression in mice carrying mutated versions of the human tau gene.

Next, and here’s the real payoff, they did the 2020s version of what was done with our alpha-synuclein discovery back in the 1990s: They used an existing database of gene expression measurements from autopsied brains with sporadic PSP and from autopsied brains with no neurodegenerative disease.  The database showed that for 63 of the 275 genes, there was an alteration similar to what was found in the stem cells from the people with FTLD-tau.

What does it all mean?  It means that drugs regulating the calcium content of brain cells may be candidates for things that might slow the degenerative process in PSP.  Such drugs would likely be convenient oral meds, including some mentioned by Dr. Minaya and colleagues that are already on the market for other conditions.  These include tramadol (for pain), ethosuximide and oxcarbazepine (for seizures), levodopa (for Parkinson’s) and nicotine* (for enriching tobacco companies).

Something else it means is that this innovative (because of its use of stem cells and large arrays of expression data) experimental approach can now be used to study any sort of brain disease that’s strongly hereditary or where there’s a rare hereditary form.

*I know what you’re thinking.  Don’t.