You already know that PSP and CBD are “pure tauopathies,” meaning that tau is the only protein consistently aggregating in the degenerating brain cells. You also know that Alzheimer’s disease has two such aggregating proteins, beta-amyloid and tau, and that problems in the former seem to induce the problems in the latter. But now there’s evidence that in PSP there’s a second protein causing the tau problem. It’s called “filamin-A” and if the evidence is correct, it’s a very big deal.
A research group from several centers in Japan led by Dr. Koyo Tsujikawa of Nagoya University encountered a pair of identical twins with PSP. They found that each man had multiple copies of a normal region of their X chromosome where 16 different genes reside. One of those 16, called “FLNA” because it encoded the protein filamin-A, was previously known to play a role in the brain cell’s internal skeleton. Of course, tau is also involved with the cytoskeleton, so the scientists focused on filamin-A before the other 15 proteins.
The paper lists 31 authors. I know two of the senior guys and can vouch that they have produced consistently excellent work for decades.
Their lab experiments showed that this mutation in the twins and their PSP are cause-and-effect rather than just coincidental. Sorry, but this gets a little tech-y:
- Autopsied brain cells from the twins with PSP showed not only the excess tau expected in PSP, but also excess filamin-A, and the two proteins aggregated into insoluble clumps in the same brain cells.
- The twins had tufted astrocytes, a tau-laden feature of PSP brain tissue found in no other disease, and those same cells had abundant filamin-A. This means that this is real PSP, as best we can define it, and not some imitator.
- Filamin-A levels were normal in autopsied brain samples from people with no brain disease and from brains of patients with CBD, AD, Parkinson’s and dementia with Lewy bodies.
- In cultured human cells, excessive filamin-A produced by adding an extra copy of the FLNA gene increases the production of tau; and reducing filamin-A production with “silencing RNA” directed at FLNA prevented excessive tau production.
- Mice engineered to over-produce tau (called “MAPT knock-ins”) did not develop high filamin-A levels, showing that in the direction of causality goes from filamin-A to tau, not the reverse.
- FLMA knock-in mice produced tau that was not only over-abundant, but qualitatively abnormal as well, with excessive attachment of phosphate groups (“hyperphosphorylation”), an important known driver of neurodegeneration in PSP and the other tauopathies.
- The genetic abnormalities in FLNA appear to damage tau by interacting with a third protein called F-actin. Genetic abnormalities in F-actin have not been found in PSP, but the function of that protein is impaired by mutations in the gene LRRK2 (“lark-two”), which are over-represented in PSP. (It was previously known that lab-induced abnormalities in F-actin can cause tau to malfunction in a way that damages brain cells, but there was no reason to think this was relevant to human tauopathies until now.)
- Among 312 patients with non-familial PSP analyzed in the new paper, none had the same mutation found in the twins (i.e., extra copies of FLNA) but there were 12 patients (4%) with other kinds of mutations in FLNA. Much lower percentages of FLNA mutations were present in patients with CBD, AD and healthy individuals.
So, what does this mean?
At the superficial level, it means that some sort of abnormalities in filamen-A could explain tau misbehavior in PSP, just as abnormalities in beta-amyloid abnormalities explain tau misbehavior in AD. Only a small minority of people (in Japan) with PSP actually have a mutation in the gene for filamen-A, but like any protein, its function may be impaired by many other things such as toxins, trauma, inflammation, and genetic or non-genetic defects in proteins with which it interacts.
At a more profound level, this new insight could mean that finding the ultimate cause of PSP should start with filamin-A or F-actin even though effective treatments for the diseases could act elsewhere, like with tau itself. Attacking a disease “upstream,” where the problem starts, is theoretically better than downstream, though the latter is closer to the actual loss of brain cells.
There are a couple of caveats:
- Mutations in FLNA have long been known to cause a developmental brain abnormality with cognitive delay. Both twins’ brains had subtle forms of that. So their PSP may not be a good model for ordinary, non-familial PSP occurring in developmentally normal individuals.
- The frequency of FLNA mutations in the 312 Japanese patients with non-familial PSP may not apply to other populations. The genetic studies of PSP in non-Japanese populations to date have not found a relationship with FLNA, but there are technical reasons for false negatives in that sort of study.
But these caveats aren’t dealbreakers at all: Regarding the second issue, remember that rare, atypical, genetic forms of neurodegenerative diseases have in the past provided very valuable insights into the cause of the common, typical, non-familial form of a disease. For example, in Parkinson’s, 20 members of an extended Italian-American family kindred with young-onset, rapid-progressive PD were found to harbor a mutation in the gene for alpha-synuclein. On further scrutiny, that protein proved to be central to all PD and trials of anti-alpha-synuclein treatments are under way. A similarly huge advance in understanding Alzheimer’s disease arose from analyzing the extra chromosome 21 in individuals with Down syndrome (trisomy 21). A search of that chromosome pointed to the amyloid precursor protein, the source of beta-amyloid, critical to all AD. In neither PD nor AD does more than a tiny fraction of patients have a mutation in their genes for alpha-synuclein or amyloid precursor protein.
Could we be at the threshold of a similarly radical advance in our understanding of PSP? Could such a paradigm shift provide targets for a drug to prevent, slow or halt PSP? We’ll find out — and I hope soon.