Tag Archives: stem cells

One RNA fits all?

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Maybe I’m streaming too many dramatic TV series these days.  My October 9 post ended in a cliffhanger, teasing an “oddball” molecule that could point the way to neuroprotective treatments for PSP and other neurodegenerative diseases. It’s called “lncRNA FAM151B-DT.” 

Quickly, some background.  The RNA most familiar to us is messenger RNA.  Its length can be anywhere from a few hundred to a few thousand base pairs (the genetic code’s “letters” for a single gene or a fragment thereof). The RNA is constructed (“transcribed”) in the cell’s nucleus from the code in DNA, then scoots out to the ribosomes, where it’s translated into a string of amino acids to build a specific protein.  But only about two percent of the DNA in our genome encodes the kind of RNA for making proteins, called messenger RNA.  Most of the rest, about 75 to 90 percent, encodes RNA that regulates DNA transcription or other cell functions.  A little of that “non-coding RNA” is “micro-RNA,” which has only about 20 to 25 base pairs, and the rest, with over 200 base pairs, is called “long, non-coding RNA.” 

Now I’ll get to the point. A research group at Washington University in St. Louis just published a paper entitled, “A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.”  They used brain cells obtained at autopsy from people who had died with PSP, Alzheimer’s, or Parkinson’s disease.  They also used skin cells from a living person with a form of frontotemporal dementia with Parkinsonism (FTDP), which is caused by a mutation in the tau gene. They transformed those (slightly) specialized skin cells into unspecialized stem cells, then transformed those into highly specialized brain cells.

The lead author of the WashU study is Arun Renganathan, PhD, a staff scientist in the Department of Psychiatry.  The senior author is Celeste Karch, PhD, associate professor of psychiatry. Disclosure: Dr. Karch and I have collaborated in research in the past and she’s a member of CurePSP’s Scientific Advisory Board, which I am honored to chair.

In each of those four disease-specific brain cell cultures, the team found FAM151B-DT reduced relative to control cells and that silencing FAM151B-DT by “knocking out” its gene increased the concentration of whichever protein was aggregating in the corresponding human disease (tau for PSP, AD and FTD-P; alpha-synuclein for PD). The mechanism was a blockage of autophagy, an important component of brain cells’ “garbage disposal” system.  The researchers found that FAM151B-DT serves as a “scaffold” to allow the tau or alpha-synuclein protein and a “chaperone” molecule called HSC70 to interact with the lysosomes, a kind of bubble in the cell fluid containing protein-degrading enzymes.  

A critical piece of the new research is that increasing the cells’ production of FAM151B-DT stimulated that system to dispose of excess tau or alpha-synuclein. That means that FAM151B-DT is the “rate-limiting step” in the process.  As you’d imagine, this suggests that increasing the concentration or efficiency of FAM151B-DT could slow or halt progression of these diseases.  All four of them.

So, how does this relate to the cliffhanger from yesterday’s post about our evolving perspective on the similarities and differences between PSP and AD?  One reason to be interested in the differences between those two is that a rare disease with limited research funding like PSP could benefit from research on treatments for AD, a very common disease with much more research funding and huge commercial potential.  Besides, we in the PSP community like when drug companies try out their AD drugs on PSP first – because of their common underlying cellular and biochemical similarities. The new paper from WashU has found one more very important similarity.

It’s not only PSP and AD.  The new paper found FAM151B-DT just as relevant to PD and FTDP.  I expect to see research soon on its relevance to others forms of FTD and to ALS, dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, and many others.  Then we wouldn’t have to worry so much about making an accurate diagnosis early in the disease course– maybe one cure will fit all!

My cure plan

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Consideration number one:


There are now ten different variants, or “phenotypes,” of PSP. The most common, PSP-Richardson syndrome, accounts for about half of those affected, and the next most common, PSP-Parkinsonism, accounts for about a third. All ten variants share the same kinds of neurofibrillary tangles, tufted astrocytes and all the other microscopic features, but their specific locations in the brain differ in emphasis. In fact, the ten have been classified into three groups: cortical PSP, subcortical PSP and PSP-RS, the last being a sort of hybrid. The differences among the ten exist only for about the first half of the disease course. After that, they all merge into what looks like PSP-RS.

What explains this (slight) diversity of anatomic predilection? We won’t know that until we know the cause of PSP, but I’ve got my theory, which I’ll tell you about after you consider this:


Consideration number two:

In 2021 I posted something about a geographical cluster of 101 people with PSP in a group of towns in northern France, which is 12 times the number expected based on surveys elsewhere. The most likely cause is the intense environmental contamination with metals dumped there by an ore processing plant. Fortunately, there have been no new cases of PSP in that area since 2016, possibly thanks to the mitigation measures taken by the local authorities starting in 2011.

In a 2015 journal publication, I did some calculations comparing the neurological features in the 92 people with PSP in the cluster at that point to those of people with “sporadic” PSP.

I found only two differences: In the cluster, the ratio of PSP-Richardson syndrome to PSP-Parkinsonism was about even, while in sporadic PSP it’s about 3:2; and the average age of symptom onset was 74.3, about a decade older than in sporadic PSP. (The area was not at all a retirement community; its age frequency structure closely resembled those of other ordinary communities in the industrialized world.) The molecular assays we performed showed no differences.


My theory:


The experts agree that the cause of most of the common neurodegenerative diseases is a genetic predisposition together with an environmental exposure. For PSP, we presently know of 14 genes, each of which has a variant in a certain percentage of the population conferring slightly elevated risk of PSP. But we don’t know how many, or what combination of those 14 are needed to set the stage for the environmental toxin. For all we know, different toxins need different numbers or combinations of PSP genetic risk factors to exert their toxicity. The only confirmed environmental risk factors for PSP are metals, but of unspecified kinds. The only other well-confirmed non-genetic PSP risk is a tendency to lesser educational attainment, which I feel is likely to act by exposing people to toxins related to manual occupations or to industrial installations or waste sites near their homes.


So, here’s how I tie all this together:


The ten PSP variants as well as the diversity of onset ages within each variant could be determined by one’s own set of PSP risk genes and by which of the possible PSP-related metals (or yet-undiscovered kinds of toxins) they encountered. The two differences between the French cluster and everyone else with PSP could be the particular types or combination of metals to which the people were exposed. That means that at its root, the cause of PSP could be an array of slightly different abnormalities at the most basic molecular level. Those differences could take the form of slightly different tau protein abnormalities across different individuals. As has already been shown, each member of the array of abnormal forms of tau (called tau “strains”) might have a predilection for a different brain area or brain cell type. That anatomic predilection would dictate the specific array of symptoms initially experienced by that individual, and that array could be different when your tau was damaged by the metals at the French site than by whatever damages tau in PSP elsewhere.


How to prove this theory:


This would take a lot of difficult research to prove, but I made a start back in 2020 with the publication of some lab experiments I suggested to a group of lab scientists at UCSF led by Dr. Aimee Kao.


She and her colleagues took stem cells from a tiny skin biopsy of a person with ordinary PSP who carried one of the known PSP risk genes. They converted the stem cells into brain cells and divided the resulting colony in two: In one half, they used the now-famous gene editing technique called CRISPR to return the variant to its normal state and left the other half with its PSP risk variant. They added chromium or nickel (the two most likely culprits at the French cluster site) to both sets of cells and found that the corrected set suffered much less damage. Furthermore, the damage involved tau aggregation and insufficient disposal of abnormal tau, just as in PSP itself.


So, now that we know 14 PSP risk genes, lab researchers could experiment with stem cells harboring different combinations thereof, along with exposure to different metals. Then, once a few such gene/metal combinations have been identified as most able to cause “PSP” in stem cells, the underlying molecular abnormalities could be worked out, drug targets identified, and drugs designed, tested, approved and prescribed.


So, you see, I’ve got it all worked out.

A warning

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Here’s something that may seem too good to be true, and in my opinion, it is.  I’m writing about it as a cautionary measure.

Researchers at Guangzhou University, China have published a case report of a man with advanced PSP who received intravenous and intrathecal (into the spinal fluid) infusions of stem cells derived from umbilical cord blood.  His symptoms had started unusually young, at age 53, and 8 years later, his PSP Rating Scale score was 73 – a typical score for that duration of disease.  He received the infusions at that point and has survived another 8 years to date with essentially the same PSPRS score. 

Although the patient is (apparently, but not explicitly) still alive and there has been no autopsy to prove the accuracy of the diagnosis, the clinical history, neuro exam and published MRI images are typical for PSP.  The subtype is probably PSP-Parkinson, as his falls didn’t start until 3 years in and he didn’t need gait aids until 2 years after that.  The authors state that the subtype was PSP-Richardson syndrome because the patient met those criteria at the time they first saw him, 8 years in.  But PSP-P usually evolves into PSP-RS in the advanced stages.  The life expectancy of PSP-P with typical onset age in the 60s is about 10 years, and for those with onset as young as age 53, would be a few years more.  So survival (to this point) of 16 years is not far from expected.

But that’s not the main problem. The main problem is that the PSP Rating Scale has a “ceiling effect.”  That is, patients progress at an average rate of 10 or 11 points per year, and once the score reaches the 70s, it stops progressing although the patients continue to survive and to worsen.  That’s because the worst possible score on many of the scale’s 28 items doesn’t capture the full level of dysfunction that can yet occur.  Another reason for the ceiling effect is that some of the 28 items don’t affect some patients severely or at all, even late in the disease course.  Examples are dystonia, tremor, irritability, emotional incontinence, horizontal eye movement loss, and limb apraxia.  So the patient of Dr. Li et al may simply have reached his PSPRS ceiling and continued to survive by virtue of the unusually good general care that study subjects typically receive.

There are some other issues:

  • There’s no objective evidence that the infused cells survived. 
  • There’s no measure of any sort of growth factor in the blood or CSF that might provide a mechanism of action of stem cells in halting an otherwise rapidly progressive disease in its tracks. 
  • There’s no functional measure of brain metabolism such as fluorodeoxyglucose PET or magnetic resonance spectroscopy to objectively document a halting/slowing of progression.
  • The 2 MRI were performed at the time of the infusions and 2 years later.  Although the authors claim “no deterioration” in the MRI over that time, the 2 sets of images do show progression of atrophy, both to my eye and by the formal measurements superimposed on the images.  The midbrain’s diameter on the before-and-after sagittal images (Fig. 1, images A-1 and B-1) declined from 11.84 mm to 10.64 mm and the pons from 21.07 mm to 19.37 mm.  Both are typical for PSP.  The before-and-after axial images (images A-2, A-3, B-2 and B-3), where the measurements seem to indicate some improvement in the atrophy, are performed different scanning planes.  That can seriously affect the simple measurements performed. In fact, comparing the 2 sagittal images shows that the patient’s head is at 2 very different tilt angles in the scanner.  That problem affects the measurements in the axial plane but not in the sagittal plane.

As Dr. Li and colleagues point out, “randomized controlled trials are needed in the future . . . “ I would advise people with PSP not to undergo this, or any, experimental procedure outside of a formal trial at a reputable academic institution.  If you’re considering it, make sure the study is listed in clinicaltrials.gov, although that by itself no guarantee of anything.  Make sure that the researchers have a track record of peer-reviewed publication in this area.  If the doctors doing the treatment are willing to use it for a wide variety of unrelated disorders, be suspicious.  If the claims omit mention of side effects or toxicity, be doubly suspicious. If there’s no mention of success in any sort of animal model, that could be a problem.  Finally, if a “research study” charges a hefty fee, stay away. (We have no evidence that this was the case for Li et al.)

We should encourage fresh ideas for the treatment of PSP and other neurodegenerative diseases.  We should not be biased against research from countries with still-developing research infrastructure and institutional safeguards.  But we should also know how to evaluate the quality of research reports and to be vigilant for signs of quackery.