The tao of tau: Part 2

As promised, here’s the second of two installments on the latest in tau-ology, at least as of the Tau2020 conference, held in February 2020. Yesterday’s post covered treatment, and today’s, everything else. There was no Tau2021, but Tau2022 is planned for February.

Tau structure and function

More is becoming known about the N-terminal domain of tau, where exons 2 and 3 are alternatively spliced (i.e., some forms of tau have the amino acid sequence encoded in the MAPT gene’s exon 2, others have those of exons 2 and 3).  This end of the protein is now suspected of controlling the spacing between microtubules, which comprise the cell’s internal skeleton and transport system.  Next to that is the “proline-rich domain,” which interacts with enzymes and with other proteins that include the WW domain.  That’s where a protein includes the amino acid tryptophan occurring in a string that regulates signaling between proteins. This is part of the new body of evidence that tau is partly a signaling protein.  (Fun fact: The single-letter amino acid abbreviation system (allegedly) assigned “W” to tryptophan because T was taken and part of the tryptophan’s molecule has a W shape.)  

The highlight of the conference was probably the keynote talk from Dr. Michel Goedert describing his group’s work on high-resolution imaging of tau using cryo-electron microscopy. (See my recent post, “A frozen treat” for details and an update.)  The bottom line was that each tauopathy has its own, very different, pattern of tau misfolding that is uniform across patients with that disorder.  That’s true even for disorders with the same isoforms, like PSP and CBD, which are both 4R (i.e., 4-repeat; having 4 microtubule-binding areas) but have radically different tau misfolding patterns.  Better understanding of these structures may point to disease-specific diagnostic and therapeutic innovations.  This starts to undermine the hope that PSP will provide the key to all tauopathies, including Alzheimer’s. For this and his other work, Dr. Goedert was awarded the $250,000 Rainwater Prize at this conference.

Post-translational modifications of tau

You know about tau phosphorylation, and the textbooks say that it can result from “stress.”  But more recent research has identified some specific causes such as brain ischemia, as from atherosclerosis; brain trauma; and excessive sodium intake.  The last works through activation of the immune system.

A recently-identified role for tau is to protect DNA in the cell’s nucleus from oxidative stress, which can result from certain toxins or from mitochondrial dysfunction.  Tau seems to help the histone proteins in the nucleus do their job of regulating access to the genome.

Abnormally phosphorylated tau in the cytoplasm can indirectly affect the function of DNA in the nucleus in many ways.  These include deranging the function of actin and microtubules, which maintain the structure of the nucleus, damaging DNA, damaging the protein portion of chromosomes, affecting RNA handling, reducing ribosome stability and encouraging DNA code rearrangements.  The next problem is to determine exactly which PTM’s do what and to develop drugs specifically targeted at those that actually cause neurodegenerative diseases. In fact, we don’t yet even know for sure that hyperphosphorylated tau causes tau aggregation in humans.

Although we know of 50 different mutations in the MAPT (i.e., the tau) gene that cause or increase risk of tauopathies, none of them is known to act via causing PTM’s.  This confirms that the pathogenesis of PSP is multifactorial and that the combination of factors differs across individuals.

Tau genetics

It has been known since 1999 that PSP is associated with a genetic variant called the H1 haplotype.  This consists of a section of chromosome 17, comprising the MAPT gene and about 15 others, that is reversed relative to the rest of the chromosome.  More recently, variants, especially the H1c subhaplotype, have been discovered that associate more strongly and specifically with PSP. The mechanism may be to allow the protein transcription machinery access to other areas of the genome where the handful of other genes associated with PSP have been identified. 

A project under the aegis of the Tau Consortium and the scientific leadership of Celeste Karch, Alison Goate and Sally Temple has created a collection of cells from 140 (and counting) volunteers with pure tauopathies such as PSP and some of their family members.  Some of the cells are fibroblasts taken from skin biopsies, others are stem cells (i.e., induced pluripotent stem cells, IPSCs) made from such fibroblasts and still others are neural cells made from those stem cells.  Some of the volunteers had single-gene causes of their illness and others had a single genetic variant that increases risk for PSP but is insufficient to cause it.  Some of the cells from the latter group with a single, identifiable mutation have had that mutation corrected using CRISPR, leaving a cell culture with only the poorly-understood genetic “background” necessary to cause the disease.  This represents a valuable tool for studying garden-variety, “sporadic” (i.e., apparently with no familial clustering) PSP. The cells are offered as a resource to carefully vetted researchers worldwide.

Mutated versions of a gene called LRRK2 (“lark-two”) are known as a group to be the strongest genetic contributors to Parkinson’s disease.  But strangely, a few people with some of LRRK2 mutations, including the most common one, develop PSP rather than PD. Now, Drs. Edwin Jabbari, Huw Morris and colleagues used samples from the UK’s Parkinson’s Disease Society Brain Bank to find that a genetic marker close to LRRK2 is associated with more rapid progression of PSP.  LRRK2 is known to affect disposal of dysfunction or excessive protein, possibly including tau. It also is involved in neuroinflammation. Both mechanisms are at or near the top of the current list of contributors to the pathogenesis of PSP.  The logical next step is to develop drugs suppressing the toxic activity of the enzyme produced by the LRRK2 gene.

The significance of the extreme predominance of 4-repeat tau in the tangles of PSP and CBD remains unclear.  (Most other tauopathies have an equal combination of 3-repeat and 4-repeat tau “isoforms,” mimicking tau in normal human brain, and a few tauopathies have predominantly 3-repeat tau.)  At Tau2020, The Rainwater Charitable Foundation awarded its early-career award to Dr. Patrick Hsu of the Salk Institute for a new technique that allows researchers to control the number of repeats in tau.  It’s based on the same general type of RNA-manipulating technology as CRISPR-Cas9, but in this case it’s called CRISPR-CasRx. It can be adapted to manipulate “alternative splicing” not only of tau, but also that of many other proteins that, like tau, have multiple isoforms. So far, the technique is only for neuronal cell cultures, but it opens up a world of potential experiments to fix the molecular variation in tau underlying PSP and CBD.

Prion-like tau propagation

We know that in cells growing in a researcher’s dish or in a mouse’s brain, misfolded tau introduced into the system can travel cell to cell, templating new copies of itself along the way.  But the details of the process and its relevance to the human tauopathies remain unclear.  In fact, in no human tauopathy has such a process been conclusively demonstrated, although it has been clearly observed in the prion protein disorders such as Creutzfeldt-Jacob disease or mad cow disease.  So, as we try to confirm the prion-like hypothesis in the tauopathies, we do have to remain open to alternative ideas to explain the spread of the disease within the brain.

A clue to why tau is secreted by brain cells could be its recently-discovered role as a local hormone or signaling molecule, to regulate the activity of brain cells and the sleep-wake cycle. However, even here the mechanisms are unclear.  There is recent evidence that tau is released from cells encapsulated in tiny membrane bubbles called vesicles.  In that case, the tau may be protected from therapeutic antibodies designed to slow the spread of tauopathies.  Additional recent evidence has found tau receptors on brain cells consisting of heparan sulfate proteoglycans, low-density lipoprotein receptor-related protein and even amyloid precursor protein.  For now, the science of tau spread remains, like most embryonic sciences, a collection of disconnected observations.

Independent of the specific molecular form or transit vehicle used by tau, imaging studies have recently shown that a prediction of the next brain region to become involved in a progressing tauopathy can be based on the involved area’s concentration of abnormal tau, its synaptic connections and its areas of direct non-synaptic contact with other cells.  Both of the latter two routes operate via active mechanisms; passive diffusion is no longer considered a factor.

Why are tau aggregates toxic?

This is a large, complicated issue, but one recently discovered clue is that brain cells containing tau aggregates, when finding themselves under stress for some other reason, signal the brain’s immune cells to come and engulf them, but without killing them. If this has the effect of protecting the tau-containing cells without preventing them from secreting their tau, then it could mean that a new tau-directed treatment could work better if coupled with a drug that inhibits the brain’s immune function.

Tau-based brain imaging

Positron emission tomography (PET) imaging using a radio-labeled glucose analog as a tracer for energy production is a standard way to help distinguish the frontotemporal disorders such as PSP, CBD and FTD from Alzheimer’s disease.  PET using a dopamine analog can distinguish the atypical parkinsonisms from Parkinson’s disease but is only available for research use.  But we have no PET-based technique to specifically identify PSP or CBD.  PET using a tau tracer is showing excellent results in distinguishing AD from other dementias, but it works poorly for PSP.  One problem is that the spatial resolution of PET is insufficient to show the tau deposits because it sticks to some other normal and abnormal molecules in the same set of neurons.  But many drug companies are developing many tau tracers and a few of them are starting to show more validity for PSP.  One, called [3H]CBD-2115, has shown good accuracy but doesn’t cross the blood-brain barrier.  However, some tweaks to the molecule or to the BBB might solve that problem.  Hopefully, it will be safe to administer and once broken down in the brain, won’t leave any radioactive remains behind for any length of time.

An exciting but early-stage development is that Genentech and AC Immune are developing an anti-tau antibody called semorinemab in tandem with a tau-directed PET tracer called [18F]-GTP1.  The PET tracer, in addition to tracking any slowing of tau aggregation, may also be useful in allowing a measurement of tau aggregation at the study baseline to predict the individual’s disease progression absent any intervention.  That, in turn, could allow a more individualized interpretation of the neuroprotective drug’s benefit.  Although that seems a good model for drug testing, it was announced in September 2021 that in prodromal and mild AD, semorinemab failed to slow progression in most of the outcome measures but did slow progression by 44% in one critical bedside test, the ADAS-Cog11.  The sister trial in moderate AD continues.  The companies have not announced plans for testing in PSP.

The NIH and the Rainwater Charitable Foundation have each created consortia to develop tau-based PET tracers for non-AD tauopathies.  The RCF effort involves the Michael J. Fox Foundation in its efforts to distinguish PD from PSP and CBD.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s