I have good news and bad news, and they’re the same piece of news.

You’ve heard of Huntington’s disease.  That’s the strongly hereditary condition that causes dementia and involuntary movements, starting at an average age of about 40 and leading to severe disability and dependency within 15 years or so.  Its most famous victim is Woody Guthrie, the folksinger/songwriter who died in 1967.  HD caused by a pathogenic variant (the word “mutation” is no longer considered appropriate) in the gene encoding the protein “huntingtin,” rendering it toxic to brain cells.

The variant in HD is a “trinucleotide repeat expansion.”   The gene has a region where the three nucleotides cytosine, adenine and guanine (CAG) are repeated multiple times.  The normal number of such repeats is less than 27.  Everyone with 40 or more repeats will develop HD and each of their children has a 50% chance of inheriting the abnormal version of the gene.  For 28 to 39 repeats, the person usually remains healthy, but the number of expansions can increase during the process of producing sperm cells or ova, putting subsequent generations at risk.  A number of other neurological diseases are caused by CAG expansions in different genes.

Huntingtin protein has several known functions in the brain, but the damage to brain cells probably is not the result of loss of any of those.  Rather, the excess number of CAG repeats encodes a an excessively long string of the amino acid glutamines. That gives the protein its toxic property, but we’re still not sure how it works or what to do about it. We do know, though, that in HD, brain cells have clumps of strands of glutamine, just as in PSP there are clumps of tau protein.

In PSP, there is no single culprit gene.  Unlike HD, PSP only very rarely runs in families and each of the 14 genetic alterations currently known to be associated with PSP confers only a slight degree of risk.  I know this looks cryptic, but here’s the current list of PSP-related genes in approximate order of discovery date: MAPT, STX6, MOBP, EIF2AK3, SLCO1A2 (two loci), DUSP10, RUNX2, LRRK2, APOE2/2 genotype, CXCR4, EGFR, GLDC, and C4A.

To this list we can now add “HTT,” the Huntington’s gene.  That’s because last month, researchers announced that they had sequenced HTT from 588 people with autopsy-proven tauopathies, including 98 with PSP, along with controls without neurodegenerative disease.  They found that while only 0.2% of the controls had at least 27 CAG repeats, for the people with PSP, the figure was 3.2% and for those with corticobasal degeneration, 2.7%.  Keep in mind that in only a small fraction of those 3.2% will the number of CAG repeats expand far enough into the toxic range to pose a risk to the children or grandchildren. 

The paper’s first author is Dr. Sergio Pérez-Oliveira and the senior author is Dr. Victoria Álvarez, both geneticists at Hospital Universitario Central de Asturias, in Oviedo, Spain, along with 21 other collaborators.  The paper appeared in Brain Pathology, a well-respected journal.

So, the bad news I mentioned is a very slight increased risk of HD occurring in future generations of families with a member with PSP.  What’s the good news?  It’s that we now know of another genetic risk factor for PSP, and it’s one that we already knew a lot about, thanks to decades of research on HD.  We can compare the long list of known actions of huntingtin in the brain to the long list of actions of the 14 other PSP-related genes. More important, we can compare the known toxic action of the excessively long strings of glutamine with the list of ways in which brain cells are damaged in PSP and look there for synergistic interactions and for drug targets to disrupt such processes.

Overall, I’d say that the good news definitely outweighs the bad news, first because statistically, the bad news is only a very small risk, and the new publication doesn’t change it – it only reveals it.  But the revelation of the good news gives PSP researchers something new to sink their teeth into in their search for a prevention and cure.